BCH / CCHMC Site Report Ingrid A. Holm, MD, MPH John Harley, MD, PhD June 29, 2015 eMERGE Steering Committee Meeting
Aim 1. Demonstrate real-time execution of phenotypic selection across two distinct pediatric institutions with disparate EMR (electronic medical record) systems as a model for ensuring phenotypic standardization and for national scalability. The need: To pool the data assets of multiple institutions into a larger virtual or physical infrastructure to facilitate discoveries that might not otherwise be detected
Results • CCHMC and BCH have created de-identified extracts of their EHRs using i2b2 which can be queried at each institution using i2b2. • The eMERGE investigators from BCH and CCHMC have used the i2b2 workbench for the development and validation of phenotype algorithms. • To enable cross-institutional query capabilities, we implemented the Shared Health Research Information Network (SHRINE) framework on a subset of the i2b2 databases (those patients with a sample in dbGaP). • SHRINE allows local queries to be broadcast simultaneously to the i2b2 instances at BCH and CCHMC, returning the aggregate results. • Used SHRINE for the eMERGE phenotypes: ADHD, Appendicitis, Asthma, Atopic Dermatitis, Autism, C. difficile, and Severe Early Childhood Obesity. • Manuscript under development – Keith Marsolo (CCHMC) and Jonathan Bickel (BCH)
Aims 3 and 4 CCHMC Cynthia A. Prows, MSN, CNS, FAAN Melanie Myers, PhD, MS, LGC BCH Ingrid A. Holm, MD, MPH Cassandra Perry, MS, CGC
Aim 3. Use return of CYP2D6 research results to explore parents responses to and use of their children’s research results and better understand the factors that influence their incidental findings decisions We hypothesized that parents of children with prior narcotic analgesia history would be more likely to share research results than parents of children without exposure histories.
Methods – CCHMC and BCH • Results of CYP2D6 genotyping returned to parents – Categories of metabolizers: • Poor metabolizer • Intermediate (CCHMC only) • Extensive (Normal) metabolizer • Ultra-rapid metabolizer – Actionable vs. non-actionable • Result delivered by telephone and parents participated in a survey – Telephone scripts for result disclosure • Subset of parents invited to participate in interview – To more fully understand responses to results • Cases vs. Controls – Cases – previously exposed to narcotics – Controls – no previous exposure to narcotics
Methods Differences between CCHMC and BCH • CCHMC – DNA samples were assayed for 20 different forms of CYP2D6 and full gene duplication, gene deletion – Follow-up telephone surveys at 3 and 12 months – Compare intent to share with reported sharing at 3 and 12 months • BCH – Hypothetical results rather than actual results • BCH Pharmacogenomic Oversight Committee deemed CYP2D6 testing not yet ready for BCH population – Equal random assignment of hypothetical results to the 3 metabolizer groups – Follow up surveys not being done
Enrollment CCHMC CCHMC Actual BCH Target BCH Actual Target Enrolled 200 203 200 99 Genotyped 200 180 N/A N/A Cases 100 92 100 (assigned) 58 Controls 100 104* 100 (assigned) 41 Actionable 133 (assigned) 61 Not actionable 67(assigned) 38 Survey at RoR 200 148 200 99 Interview at RoR Up to 60 61 Up to 60 Reached saturation at 22 Cases Up to 30 30 Up to 30 12 Controls Up to 30 31 Up to 30 10 Survey at 3 months 100 80 N/A N/A Survey at 12 months 100 49 N/A N/A *So far, 12 parents who were enrolled as controls, became cases by time results returned and survey conducted (case = parent of child exposed to opioid)
Parent/Doctor Can Use Results to Care for Child 100% 0 0 0 1 90% 80% 70% 60% Strongly or Somewhat 50% 100 100 100 99 Disagree 40% Strongly or Somewhat 30% Agree 20% 10% 0% Parent Parent Doctor Doctor Boston Cincinnati Boston Cincinnati
Likelihood of Sharing Results 100% 0 2 90% 27 32 80% 48 51 70% 60% 50% 100 98 40% 73 68 30% 52 49 20% 10% 0% Doctor Boston Doctor Pharmacist Pharmacist Child Boston Child Cincinnati Cincinnati Boston Cincinnati p < 0.01 Extremely or Somewhat Likely Not Very or Not At All Likely
Qualitative Interview Preliminary Results • Despite CYP2D6 results, parents perceived their children as normal. • Parents’ emotional reactions were influenced by their expectations about the results.
Aim 3 Preliminary Conclusions • Parents feel they and their child’s physician can use the child’s CYP2D6 research result to provide care for child – Child’s previous exposure to opioids and actionability of research result may be associated with perceived utility of result • Parents report that they are likely to share their child’s CYP2D6 research result with their child’s physician – Actionability of CYP2D6 research result was associated with parents likelihood of sharing the result with the child’s physician or pharmacist but not with the child
Work in Progress • Finishing surveys – BCH – initial surveys – CCHMC – follow-up surveys at 3 and 12 months • Interviews completed and coded • Manuscripts – Qualitative interviews – Joint manuscript to be submitted this summer – Manuscripts under development • The type of information parents request when being told a pharmacogenetic research result • Factors that contribute to differences regarding intent to share CYP2D6 results • Similarities and differences between parents’ responses when told actual versus hypothetical CYP2D6 results
Aim 4. To explore clinician perceptions of pharmacogenetic research results after EHR integration • To date, CCHMC has distributed surveys to 67 unique providers and 32 have responded. – Survey distribution requires participant permission at 3 month follow up survey. • BCH distributing hypothetical results and a modified survey to 32 pediatricians, 7 have responded.
CCHMC Physician Surveys • 57 out of 63 parents gave permission at 3 month follow up to send results to child’s provider • 42 surveys with results (39 EM, 1 IM, 1 PM, I UM) mailed & 22 providers responded – 41% felt result could potentially improve child’s health outcomes, 55% unsure – 82% plan to enter result in child’s EMR – 91% agree research results that could potentially improve health outcomes should be returned to research participant • Will assess for differences between physicians who receive actual CYP2D6 research results and physicians who receive hypothetical results
Aim 4 Preliminary Conclusions • Providers consider it important to return research results that could potentially improve their patients’ health outcomes
Acknowledgements Aims 3 and 4 eMERGE Team CCHMC eMERGE Team BCH Cynthia A. Prows, MSN, CNS, FAAN Ingrid Holm, MD, MPH Melanie Myers, PhD, MS, LGC Cassandra Perry, MS Matt Veerkamp, BA Ariel Chandler, MS Sarah Adelsperger, BA Wendy Wolf, PhD Beth Cobb, MBA Sonja Ziniel, PhD Laura Gaines, MS Diane Kissell, BA John Lynch, PhD Brooke McLaughlin, MS Pharmacogenetics Survey Andrea Murad, BA Susanne Haga, PhD Ashton Roach, BA Carrie Weaver, MS Kejian Zhang, MD, MBA Parents / Participants Nicole Dalessandro, BA Rachel Supinger, BA
Aim 2: Contribute to phenotype selection and perform the GWAS & PheWAS selected by the eMERGE II Steering Committee
Aim 2: Contribute to phenotype selection and perform the GWAS & PheWAS selected by the eMERGE II Steering Committee • - Early Childhood Obesity – Completed ( 2 papers in development ) • - Autism – Completed ( revisions requested JAMIA ) • - Appendicitis – Completed • - CCHMC/BCH-PheWAS study – Completed ( paper published ) • - QTL- GWAS analyses for Obesity-BMI% – Completed ( paper published ) • - ADHD – Completed (secondary validation) • - Asthma – Completed (secondary validation) • - Atopic Dermatitis – Completed (secondary validation) • - C-Diff – Completed (secondary validation) • - GERD – Completed (secondary validation) • - Bilirubin and LFTs- Completed- ( draft circulating)
Early Childhood Obesity (ECO) • Algorithm final, tested (PPV=90%), validated (Vandy, CHOP) – Geisinger – site specific implementation & future projects • EMR-linked childhood BMI. Namjou et al 2013 – COL6A5, a novel association , p<10E-8, MAF ~5%. – FTO, MCR4, CCK, IL15, LRP1B, TMEM18, all previously known, also identified 2 for the first time in pediatric cases. • Two manuscript concept sheets for early obesity – Algorithm construction (Lingren) – Clinician variation in EMR documentation (Thaker, Brady) • Organizing for Sequencing and GWAS for binary trait and QTL. – Controls, <85% BMI; cases, >99% BMI (Vanderbilt [cases=109, controls=369]; CCHMC [cases=130, controls = 478] [total=1,086]).
2860 subjects, 28% obese 9.8 yrs, average age OR=1.61 for FTO Best FTO variant, p<10 -8 BMI in Children Extracted BMI from the EHR & performed QTL Namjou et al Front Genetics 10.3389, 2013
>5 yr slope=0.25/A allele <5 yr slope= 0.075/A allele Namjou et al Front Genetics 10.3389, 2013
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