Bernie LaSalle

Alternating hemiplegia of childhood: Retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers’ questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Development of a HIPAA-compliant environment for translational research data and analytics

High-performance computing centers (HPC) traditionally have far less restrictive privacy management policies than those encountered in healthcare. We show how an HPC can be re-engineered to accommodate clinical data while retaining its utility in computationally intensive tasks such as data mining, machine learning, and statistics. We also discuss deploying protected virtual machines. A critical planning step was to engage the universitys information security operations and the information security and privacy office. Access to the environment requires a double authentication mechanism. The first level of authentication requires access to the universitys virtual private network and the second requires that the users be listed in the HPC network information service directory. The physical hardware resides in a data center with controlled room access. All employees of the HPC and its users take the universitys local Health Insurance Portability and Accountability Act training series. In the first 3 years, researcher count has increased from 6 to 58.

Initiation and management of a pediatric multicenter drug trial by an academic center

Abstract Background: Although the number of prospective pediatric drug trials has increased in the past few years, there are still fewer studies done in pediatric patients than in adults. Such studies are critical for determining the safety, efficacy, and appropriate dosing of drugs in children. Objectives: This article outlines the difficulties encountered in initiating and performing multicenter drug studies in children and offers recommendations for developing and conducting such studies. Methods: We reviewed existing literature in pediatric drug trials, searching PubMed and reviewing topics in such trials, and analyzing our own experience. Results: Recent legislation offers financial incentives to pharmaceutical companies to conduct clinical trials in pediatric patients; however, obstacles to the successful initiation and completion of such trials still exist. Pediatric centers are often inexperienced at developing clinical trial protocols and applying for research grants. In addition, many drugs cannot be administered at appropriate doses to smaller patients in tablet or capsule form, making it necessary to develop new formulations. Furthermore, parents may be reluctant to allow their children to participate in placebo-controlled trials. Pediatricians interested in developing drug trials must plan carefully to anticipate all of the budgetary, staffing, regulatory, and enrollment problems that may arise over the course of such a trial. Conclusions: More trials are needed to determine the safety, efficacy, and optimal doses of new drugs and of drugs already used off-label to treat pediatric patients. The financial incentives offered by legislation provide additional reasons for pediatricians and industry to work together to perform drug trials in pediatric patients.

2507: Towards a scalable informatics platform for enhancing accrual into clinical research studies

OBJECTIVES/SPECIFIC AIMS: Issues with recruiting the targeted number of participants in a timely manner often results in underpowered studies, with more than 60% of clinical studies failing to complete or requiring extensions due to enrollment issues. The objective of this study is to develop and implement a scalable, organization wide platform to enhance accrual into clinical research studies. METHODS/STUDY POPULATION: We are developing and evaluating an informatics platform called Utah Utility for Research Recruitment (U2R2). U2R2 consists of 2 components: (i) Semantic Matcher: an automated trial criterion to patient matching component that also reports uncertainty associated with the match, and (ii) Match Delivery: mechanisms to deliver the list of matched patients for different research and clinical settings. As a first step, we limited the Semantic Matcher to utilize only structured data elements from the patient record and trial criteria. We are now including distributional semantic methods to match complete patient records and trial criteria as documents. We evaluated the first phase of U2R2 based on a randomized trial with a target enrollment of 220 participants that compares 2 treatment strategies for managing back pain (physical therapy and usual care) for individuals consulting a nonsurgical provider and symptomatic <90 days. RESULTS/ANTICIPATED RESULTS: U2R2 identified 9370 patients from the University of Utah Hospitals and Clinics as potential matches. Of these 9370, 1145 responded to the Back Pain study research team’s email or phone communications, and were further screened by phone. In total, 250 participants completed a screening visit, resulting in the current study enrollment of 130 participants. Forty-three of 1145 patients refused to participate, and 50 participants no-showed their screening visit. DISCUSSION/SIGNIFICANCE OF IMPACT: A recruitment platform can enhance potential participant identification, but requires attention to multiple issues involved with clinical research studies. Clinical eligibility criteria are usually unstructured and require human mediation and abstraction into discrete data elements for matching against patient records. In addition, key eligibility data are often embedded within text in the patient record. Distributional semantic approaches, by leveraging this content, can identify potential participants for screening with more specificity. The delivery of the list of matched patient results should consider characteristics of the research study, population, and targeted enrollment (eg, back pain being a common disorder and the possibility of the patient visiting different types of clinics), as well as organizational and socio-technical issues surrounding clinical practice and research. Embedding the delivery of match results into the clinical workflow by utilizing user-centered design approaches and involving the clinician, the clinic, and the patient in the recruitment process, could yield higher accrual indices.

Erratum: Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry (PLoS ONE (2015) 10:8 (e0137370) (doi:10.1371/journal.pone.0137370))

Louis Viollet, Gustavo Glusman, Kelley J. Murphy, Tara M. Newcomb, Sandra P. Reyna, Matthew Sweney, Benjamin Nelson, Frederick Andermann, Eva Andermann, Gyula Acsadi, Richard L. Barbano, Candida Brown, Mary E. Brunkow, Harry T. Chugani, Sarah R. Cheyette, Abigail Collins, Suzanne D. DeBrosse, David Galas, Jennifer Friedman, Lee Hood, Chad Huff, Lynn B. Jorde, Mary D. King, Bernie LaSalle, Richard J. Leventer, Aga J. Lewelt, Mylynda B. Massart, Mario R. Mérida, II, Louis J. Ptáček, Jared C. Roach, Robert S. Rust, Francis Renault, Terry D. Sanger, Marcio A. Sotero de Menezes, Rachel Tennyson, Peter Uldall, Yue Zhang, Mary Zupanc, Winnie Xin, Kenneth Silver, Kathryn J. Swoboda