ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Inborn Errors of Metabolism Collaborative: large-scale collection of data on long-term follow-up for newborn-screened conditions Susan A. Berry, MD1, Nancy D. Leslie, MD2, Mathew J. Edick, PhD3, Sally Hiner3, Kaitlin Justice3 and Cynthia Cameron, PhD3; for the Inborn Errors of Metabolism Collaborative Purpose: The Inborn Errors of Metabolism Information System on the recommended uniform screening panel; 4 conditions have (IBEM-IS) collects data on the clinical history of inborn errors of more than 100 subjects enrolled. Median follow-up time for subjects metabolism (IBEMs). The IBEM-IS is accessible to metabolic clinics with more than one visit (n = 898) is 1.5 years (interquartile range = nationwide and seeks to (i) influence clinical management of affected 2.2 years). Subjects with critical conditions are more likely to have individuals and (ii) provide information to support public health emergency letters and sick-day plans. Mortality was exclusive to chil- decision making. dren with critical conditions. Methods: Thirty centers in 21 states are enrolling persons with Conclusion: Large-scale prospective data can be collected for indi- newborn-screened conditions, collecting information on diagnosis viduals with rare conditions, permitting enhanced decision making and treatment at the time of enrollment and all subsequent visits. for clinical management and supporting decision making in public Prospective data are collected using electronic capture forms allow- health newborn screening programs. ing aggregation of information regarding outcomes for individuals affected with IBEMs. Genet Med advance online publication 19 May 2016 Results: A total of 1,893 subjects have been enrolled in the IBEM-IS, Key Words: inborn errors of metabolism; natural history; newborn and more than 540,000 individual data points have been collected. screening; Newborn Screening Translational Research Network; Data collection has been initiated for subjects with 41 of 46 ­conditions public health INTRODUCTION with newborn-screened conditions. The Inborn Errors of Nearly every baby born in the United States is tested soon Metabolism Collaborative (IBEMC) has overcome this bar- after birth for inborn errors of metabolism (IBEMs) through rier by creating a data-collection system that is accessible to newborn blood spot screening (NBS). This screening identi- ­metabolic clinics nationwide. fies rare and potentially life-threatening conditions and offers The IBEMC developed1 and is using a robust data-collection the opportunity for early intervention to improve outcomes for tool to document the clinical history of rare IBEMs detected by affected individuals. After more than 50 years of NBS, however, NBS. Our interest in initiating the Inborn Errors of Metabolism few screened conditions have an evidence base to justify consis- Information System (IBEM-IS) was twofold: (i) to influence tent clinical practice strategies. the clinical management and care of affected individuals and In current practice many interventions used to treat and (ii) to provide information to support decision making in manage these conditions are determined empirically, based public health. Here, we present an update on the progress of on the experience of the clinician. Meanwhile, emerging new large-scale data collection and provide information about the treatments and interventions prompt continued evolution character and potential utility of the information collected. of care practices, patients and their caregivers seek clear and consistent advice concerning effective interventions, and third- MATERIALS AND METHODS party payers and clinicians want evidence of best practices and Creating the IBEM-IS clinical utility regarding the diagnosis, management, and long- The development of a collaborative, interactive group of clini- term outcomes of these conditions. Because newborn-screened cians was essential to the data-collection efforts. Creation of this IBEMs are rare, an evidence base for decision making cannot be group was supported by the Region 4 Genetics Collaborative accumulated in a single center. Collaboration across multiple managed by the Michigan Public Health Institute (MPHI). centers is necessary to systematically collect data on the man- Clinicians and public health representatives from the Region 4 agement, treatment, and long-term outcomes of individuals states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, 1Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; 2Department of Pediatrics, Cincinnati Children’s Medical Center, Cincinnati, Ohio, USA; 3Michigan Public Health Institute, Okemos, Michigan, USA. Members of the IBEMC are listed in the Acknowledgments. Correspondence: Susan A. Berry ([email protected]) Submitted 24 December 2015; accepted 24 March 2016; advance online publication 19 May 2016. doi:10.1038/gim.2016.57 1276 Volume 18 | Number 12 | December 2016 | Genetics in medicine IBEMC: NBS long-term follow-up | BERRY et al ORIGINAL RESEARCH ARTICLE and Wisconsin) formed a workgroup to define a set of critical have received human subjects protection approval from their elements needed for ongoing follow-up1 and initiated data col- institution. Funding from the Eunice Kennedy Shriver National lection for one condition, medium-chain acyl-CoA dehydroge- Institute of Child Health and Human Development, National nase (MCAD) deficiency. Additional disorders were added in a Institutes of Health, supports 13 centers; other centers are sup- stepwise fashion to incorporate additional fatty acid oxidation ported by their Regional Genetics Collaboratives. Additional disorders and additional categories of newborn-screened con- centers continue to be engaged at their request; four centers are ditions (aminoacidopathies, organic acidemias, and others). currently in the process of obtaining human subjects approval. The Region 4 workgroup subsequently defined condition-spe- cific elements for all of the primary and secondary metabolic Data analysis conditions identified on the recommended uniform screening Data were exported from the IBEM-IS into SPSS statistical soft- panel.2 The first subject was enrolled in 2007; subjects with other ware for tabulation and analysis. Frequencies of emergency let- conditions were enrolled as additional data elements became ters, sick-day plans, and 24-h on-call contact information were available. This constituted the first version of the IBEM-IS. compared using chi-squared tests. Simultaneous national efforts with a joint workgroup of the Newborn Screening Translational Research Network (NBSTRN) RESULTS and the National Coordinating Center for the regional collabor- The IBEM-IS atives brought together expert clinicians to further define com- The IBEM-IS is a robust data-collection tool used to collect mon data elements for long-term follow-up. Incorporating the demographic and clinical data from patients with IBEMs and data elements from the Region 4 Workgroup and other expert their clinicians at metabolic specialty centers in multiple states input, common data elements and condition-specific elements (Figure 1). The data-collection instruments in the IBEM-IS were confirmed for metabolic conditions on the recommended are divided into three types: intake forms (n = 5), visit forms uniform screening panel. These elements were translated into (n = 8), and special forms (n = 4). At the time a subject agrees electronic data capture forms using Research Electronic Data to participate, information is collected using Web-based intake Capture (REDCap) by the IBEMC in collaboration with the forms that include demographics, family history, health his- NBSTRN. REDCap is a secure, Web-based application that pro- tory, newborn screening assessment, and initial testing evalua- vides (i) an intuitive interface for validated data entry; (ii) audit tion. In general, subjects are consented during a clinic visit. As trails for tracking data manipulation and export procedures; a result, the intake enrollment forms and the initial visit data (iii) automated export procedures for seamless data downloads forms are both completed at the time of enrollment. Visit forms to common statistical packages; and (iv) procedures for import- include information about interval health history, findings, ing data from external sources.3 The resulting data system is the ancillary care, laboratory studies, management, pharmacother- Longitudinal Pediatric Data Resource (LPDR), a support tool apy, and nutrition. Each time the enrolled individual returns that is available to researchers and provided by the NBSTRN. to the clinic, an additional set of visit forms is completed. This When REDCap forms became available, all data in the original allows monitoring of interval activities such as hospitalization, version of the IBEM-IS was mapped to the new data elements emergency department visits, changes in educational or other and transferred from its original site to servers at MPHI. The social service support, and nutritional and pharmacological IBEM-IS currently uses the LPDR data-collection forms and interventions. Special forms are used to capture information data dictionary.4 Data are collected using an instance of REDCap about unique clinical interventions or circumstances such as at MPHI; data are stored securely at MPHI. pregnancy (1,305 elements), dialysis (93 elements), transplan- tation (93 elements), and study status (53 elements). Human subjects As of 27