NERIC 2017 August 16-18, 2017 Burlington, Vermont Single Disease Centered COBRE… A Novel Approach A. I. duPont Hospital for Children

The Delaware Comprehensive Sickle Cell Research Program A Center of Biomedical Research Excellence

Sickle Cell Disease Archetype of the Single Gene Disease. Mutation in the gene encoding the βchain of hemoglobin with substitution of valine for glutamic acid at position 6 (βGlu 6 Val). HbS polymerizes in its deoxy conformation due to a hydrophobic interaction between HbS strands, with the formation of long fibers. Process is indispensable to disease pathophysiology, but is an insufficient determinant of phenotype.

Sickle Cell Disease FACTS: >200,000 babies born annually with sickle cell disease in Africa 10% of African-Americans carry the trait 1:400 African-Americans born with the disease Annual hospitalization costs ~$1 billion

The sickle red blood cell (SS RBC) as source of multiple pathophysiologic pathways

Sickle Cell Disease Project 2 Project 1 ADMIN CORE Basic Science: Project 1 Gene Editing Clinical Science: Project 2 Phase I/II Clinical Trial CDM CORE Delaware Comprehensive Sickle Cell Research Center Pilot 2 Pilot 1 Psycho-Soc Science: Project 3

The Clinical and Data Management Core Core Director: E. Anders Kolb, MD I have nothing to disclose.

Vaso-Occlusive Crisis Clinical and Data Management Core Well Visit Data Elements Well Visit Category Example of Smart Data Elements Background Information genotype, baseline hemoglobin, baseline reticulocyte, WBC Medication hydroxyurea, dose, weight, missed doses per week Medical Imaging TCD, MRI, liver iron, cardiac iron, spleen iron, ultrasounds, MRCP Cardiovascular Studies Echo exam, EKG exam Pulmonary Procedures PFTs, sleep studies Immunization Complete records Surgical Procedures splenectomy, cholecystectomy, central venous access, joint surgery, cerebrovascular Team 1 EHR Workflow Health Informatics Knowledgebase/Web design Clinical Care (MD, PNP, RN) Clinical Research Associates Bioinformatics Quality of Care/Outcomes Standardized documentation of health maintenance and adverse event Workflow efficiency Intrinsically sustainable EHR tools Adverse Event Grading Grade Vaso-Occlusive Crisis Acute Chest Syndrome 1 Outpatient, no opioids Fever/Cough/New infiltrate/Hypoxia 2 Outpatient, opioids Grade 1 with therapeutic transfusion and/or mild distress 3 Inpatient, less than 5 days Grade 1 with non-invasive ventilation and/or moderate distress 4 Inpatient, more than 5 days Critical care management 5 Death

Clinical and Data Management Core Team 1 1000 Adverse Events EHR Workflow Health Informatics Knowledgebase/Web design Clinical Care (MD, PNP, RN) Clinical Research Associates Bioinformatics 500 Quality of Care/Outcomes Standardized documentation of health maintenance and adverse event Workflow efficiency Intrinsically sustainable EHR tools Vaso-occlusive Crisis Acute Chest Syndrome Sepsis Aplastic Crisis Splenic Sequestration Stroke Cholecystitis Co-morbidities Health Maintenance

Computable Phenotypes Clinical and Data Management Core Team 2 ICD9/ICD10 based classification system 500,912 patient records 434 identified with sickle cell disease 288 True Positives 146 False Positives Computable Phenotypes Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Computable Phenotypes AE Reporting Population Trends Predictive modeling

Computable Phenotypes Clinical and Data Management Core Team 2 Computable Phenotypes Observational Medical Outcomes Partnership Common Data Model Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Computable Phenotypes AE Reporting Population Trends Predictive modeling

Computable Phenotypes Clinical and Data Management Core Team 2 ICD9/ICD10 based classification system 500,912 patient records 434 identified with sickle cell disease 288 True Positives 146 False Positives Computable Phenotypes Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Computable Phenotypes AE Reporting Population Trends Predictive modeling Observational Medical Outcomes Partnership Common Data Model ICD9/ICD10 based classification system 500,912 patient records 281 identified with sickle cell disease 250 True Positives 31 False Positives

Computable Phenotypes Clinical and Data Management Core Team 2 Team 1 and Team 2 merged Team 1 - Supplies the gold-standard to train the computable phenotype algorithm Team 2 - Linear Discriminant Analysis based on 20 features in a leave-one-out cross validation approach. Computable Phenotypes Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Computable Phenotypes AE Reporting Population Trends Predictive modeling sb+ sb0 sc ss 20 1 3 5 85 2 134 Correctly classifies sickle cell patients by genotype 96.4% of time

Computable Phenotypes Clinical and Data Management Core Team 2 Team 1 and Team 2 merged Team 1 - Supplies the gold-standard to train the computable phenotype algorithm Team 2 - Linear Discriminant Analysis based on 20 features in a leave-one-out cross validation approach. Computable Phenotypes Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Highly Discriminating Transcranial Doppler Sickle cell-hemoglobin C without crisis Sickle cell-thalassemia without crisis Hemoglobin C percentage Hemoglobin S percentage Hemoglobin A percentage Amoxicillin Less Discriminating Hemoglobin SS Blood count; reticulocyte, manual Hemoglobin fractionation Hydroxyurea Computable Phenotypes AE Reporting Population Trends Predictive modeling

Computable Phenotypes Clinical and Data Management Core Team 1 Team 2 Team 3 EHR Workflow Computable Phenotypes Genomics Health Informatics Knowledgebase/Web design Clinical Care (MD, PNP, RN) Clinical Research Associates Bioinformatics Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Epic Programming Knowledgebase/Web design Clinical Care (MD, PNP, RN) Bioinformatics Computational Biology Quality of Care/Outcomes Standardized documentation of health maintenance and adverse event Workflow efficiency Intrinsically sustainable EHR tools Computable Phenotypes AE Reporting Population Trends Predictive modeling EHR/Knowledgebase Integration with genomics Predictive modeling Sustainability Generalizability Integration