Prabhu RV Shankar, MD, MS UC Davis Health Twitter: # rvpshankar

1. Novel Approaches to Identifying Rare Diseases Using Electronic Health Record data, Mabry Syndrome as an example Session Number: S106 Prabhu RV Shankar, MD, MS UC Davis Health Twitter: #rvpshankar

2. Disclosure • I and my spouse/partner have no relevant relationships with commercial interests to disclose. AMIA 2017 | amia.org

3. Learning Objectives • After participating in this session the learner should be better able to: • Develop a general approach to identify patients with rare genetic diseases - Mabry syndrome a rare genetic disease as an example, using stored Electronic Health Record (EHR) data to facilitate cohort definition for further research AMIA 2017 | amia.org

4. Organization of the talk • Background • Rare disease diagnosis and problems with diagnosis • Problems with searching Electronic Health Record (EHR) Data & other data sources • Mabry Syndrome • Methods • Lab test abnormalities • Other associated co-morbidities • Search methods & filtering/ sorting/ review Results and next steps AMIA 2017 | amia.org

5. Rare Diseases • Many rare diseases are not documented or missed during routine patient care • Reasons for missing rare diseases include: • Nonspecific presentation during childhood • Poorly defined or evolving case definitions • Lack of awareness about the rare diseases among healthcare professionals • Unavailability of sensitive and specific commonly recognizable biomarkers • Requires special diagnostic workup AMIA 2017 | amia.org

6. Mabry syndrome • Also called Hyperphosphatasia with Mental Retardation Syndrome (HPMRS): • Autosomal recessive disease (most Inherited Errors of Metabolisms!) • Increased serum levels of alkaline phosphatase (ALP) • Developmental delay • Intellectual disability • Seizures Image downloaded from: http://medicalxpress.com/news/2016-04-genetic-intellectual-disability.html AMIA 2017 | amia.org

7. Mabry syndrome (HPMRS), Molecular Basis Glycosyl-phosphosphatidyl-inositol (GPI) anchor Images downloaded from: http://medicalxpress.com/news/2016-04-genetic-intellectual-disability.html & http://spaceref.com/international-space-station/nasa-space-station-on-orbit-status-27-january-2017---jaxa-htv-6-released-will-perform-experiments.html AMIA 2017 | amia.org

8. GPI Anchor Biosynthesis • GPI is a Glycolipid • Glycosylphosphatidylinositol • posttranslational modification 1st >50% -------- Carbohydrate linker Phosphatidylinositol Fatty acids http://www.biken.osaka-u.ac.jp PIGY

9. Mabry syndrome, continued • This genetically heterogeneous condition is often missed due: • lack of awareness about the disease • Misinterpretation of the elevated ALP level, a unique biomarker of this disease, attributing it as an effect of growing bone or liver dysfunction without further evaluation • There is no comprehensive gene panel for testing AMIA 2017 | amia.org

10. Normal Alkaline Phosphatase Levels AMIA 2017 | amia.org

11. Causes of Elevated ALP Levels • Physiological: • Infancy/ Puberty/ Pregnancy/ Intestinal isoenzymes Bone disease: • Hyperparathyroidism/ Rickets/ Osteomalacia/ Paget’s/ Osteomyelitis • Seizures • Hepatobiliary disease: • Hepatitis/ Cholestasis/ Cirrhosis • Others: • Malignancies (Carcinoma of bronchus) • Transplants • Inherited Errors of Metabolism (IEMs)!!!! AMIA 2017 | amia.org

12. EHR Data and Search Strategy • ICD Diagnosis codes for Mabry Syndrome! • ICD-9-CM 319 and ICD-10-CM F79: Unspecified intellectual disabilities • Free text search deemed not useful • Search Strategy • ALP>500U/L • All Diagnoses • Filter based on combination of selected diagnoses AMIA 2017 | amia.org

13. Mabry Syndrome - Phenotype

14. ICD 9 Coverage in the EHR

15. Results AMIA 2017 | amia.org

16. Associated Diagnoses 4124 ICD based associated diagnoses in the EHR!

17. Patient Inclusion & Exclusion *Excluded patients with bone fracture, hepatitis, hepatomegaly, confirmed genetic diseases (e.g.,Down syndrome), organ transplant of any kind, liver disease, or cancer ** Associated Neurological diagnoses or unexplainable persistently elevated ALP

18. Processing - Bone diseases - Liver diseases - Confirmed genetic disease (e.g. Down syndrome) - Organ transplants - Cancer - Neurology Appointment - Neurology Notes - Persistently high ALP - Chart Review Manual 2823 Fox cub uses old conveyor belt as a slide 24 158 2162 Image downloaded from: http://www.mirror.co.uk/news/uk-news/fox-cub-uses-old-conveyor-149641

19. Outcomes

20. Lessons Learned • An important outcome of this study is increased awareness among clinicians about persistent elevation of ALP in Mabry and the need for further investigation in children if common causes of elevated ALP are ruled out • Many patients with persistent elevation of ALP levels, with normal Calcium and Phosphate levels appear to have Vitamin D deficiency • Literature about Mabry Syndrome prevalence and it’s phenotype (persistent ALP elevation) are limited and sometimes conflicting • Need for establishing and updating Mabry Syndrome gene panels • Need for studies about natural history of patients with Mabry Syndrome • Difficulty recruiting patients for genetic studies – followed up by pediatricians or neurologists 20

21. Algorithm for Genetic Testing for Mabry 1. Persistently elevated ALP 2. Mabry syndrome phenotype, especially neurological manifestations 3. No diseases with Liver, bone, organ transplantation, cancer or medications that elevate ALP 4. Normal Calcium/ Phosphate 5. Request Vitamin D A. If low, treat and repeat Vitamin D levels after 2 months B. If normal, recheck in 2 months to rule out transient Hyperphosphatasia in infants 6. If persists to have elevated ALP and normal Vitamin D levels, consider genetic testing

22. Future Steps • Expand search for Mabry patients in patients who had persistent elevation of ALP above the age – gender reference range and 1000 U/L • Cohorts from UC Davis and UC System • Defining Common Data Elements and Semantic Tagging • Predictive Modeling to identify features & minimum phenotype set for Mabry diagnosis • Mabry Network 22

23. Question: Diagnosis to consider if: • 13y F with developmental delays and seizures • Persistently elevated ALP • Normal Calcium, Phosphate, • Vit D & transaminase levels • Liver disease • Bone disease • Mabry syndrome • Paget’s disease of bone • Laboratory error AMIA 2017 | amia.org

24. Acknowledgements • Emory University Medical Genetics Team • Hong Li, MD, PhD • Rachael Logan • Allison Foley, MS • Eleanor Botha, MS 24

25. AMIA is the professional home for more than 5,400 informatics professionals, representing frontline clinicians, researchers, public health experts and educators who bring meaning to data, manage information and generate new knowledge across the research and healthcare enterprise. AMIA 2017 | amia.org

26. Thank you! Email me at: rvpshankar@ucdavis.edu

27. Flow cytometry (Dr. Cheng-Kui Qu from Aflac center) What other biomarkers can be used to further support Mabry Syndrome? “Flow cytometry can determine whether the patient has reduced (partial) expression of GPI proteins (ie, PNH type II) or complete absence of GPI proteins (ie, PNH type III).” Dr. Charles Repetti is working on it Surface expression of GPI-APs on granulocytes

28. What other biomarkers can be used to further support Mabry syndrome? • Decreased phosphorylated metabolites: • Phosphoethanolamine(PEA) • Inorganic pyrophosphate (PPi) • Pyridoxal-5'-phosphate (PLP) • Unknown metabolites • Other GPI-APs / metabolites elevation Metabolomics study? Proteomics study?