Joanne Odenkirchen

Randomized Trial of Thymectomy in Myasthenia Gravis

BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Common data elements in epilepsy research: Development and implementation of the NINDS epilepsy CDE project

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience‐related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start‐up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS‐funded clinical research, and where appropriate, facilitate the development of evidenced‐based guidelines and recommendations. Epilepsy‐specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy‐specific CDE initiative can be viewed as part of the larger international movement toward “harmonization” of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Standardizing the Structure of Stroke Clinical and Epidemiologic Research Data The National Institute of Neurological Disorders and Stroke (NINDS) Stroke Common Data Element (CDE) Project

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is “to reduce the burden of neurologic disease.” Supporting translational, clinical, and population research in stroke is fundamental to this mission, as stroke is the single greatest nervous system cause of death and disability, both in the United States and worldwide.(1, 2) (3) Accordingly, the NINDS supports a diverse array of translational, clinical trial, epidemiologic, and additional patient-oriented research in cerebrovasular disease, which have had a substantial beneficial effect upon health policy, clinical care, and patient outcomes.(4) However, the fullest potential benefit of these research endeavors has not been realized due to the absence of uniform, widely-accepted formats to characterize demographic, disease, care process, and outcome variables. Data elements are often characterized in varying manners in different studies, hampering cross-study comparisons, recognition of population differences, data-sharing, and pooled analyses. To harmonize data collected across diverse translational, clinical, and population studies, NINDS began the Common Data Element (CDE) Project in 2006.(5) The project aims to standardize naming, definitions, data structure, and response options for all variables commonly employed in NINDS-funded patient and population research. The CDE project complements study-level guidelines from the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network.(6) However, where EQUATOR guidelines focus on the reporting of study level results, the CDE Project focuses on the collection and reporting of individual variable level results, providing guidance for data collection, and facilitating data sharing, at a more granular, patient level. The overall CDE Project has four primary goals: 1) disseminate standards for the collection of data from participants enrolled in studies of neurological diseases; 2) create easily accessible data-collection tools for investigators that are ready to use “off the shelf”; 3) encourage focused and simplified data collection to reduce burden on investigators and practice-based clinicians to increase clinical research participation; and 4) improve study quality and reduce cost of data entry, cleaning and analysis by providing uniform data descriptions and tools across NINDS-funded clinical studies of treatment for neurological diseases.(5, 7) The anticipated benefits of the CDE Project are multiple, and include: 1) rapid and efficient study start-up by allowing investigators access to appropriate data elements, definitions, and case report form templates; 2) improved patient safety by facilitating development of common report templates that can be submitted to oversight committees such as Data and Safety Monitoring Boards (DSMBs); 3) enriched data sharing and data aggregation by employing standard definitions and common forms; and 4) wide adoption of common outcome measures (e.g., functional, cognitive) that may be relevant across the neurological diseases.(5, 7) The CDE Project first developed a set of General CDEs commonly collected in all neuroscience clinical studies, including demographic information, medical history data, medication use, and data needed for safety reporting.(8) Next, development of disease-specific CDEs was undertaken. This paper describes the process and outcome for the development of Stroke CDEs.Background and Purpose— The National Institute of Neurological Disorders and Stroke initiated development of stroke-specific Common Data Elements (CDEs) as part of a project to develop data standards for funded clinical research in all fields of neuroscience. Standardizing data elements in translational, clinical, and population research in cerebrovascular disease could decrease study start-up time, facilitate data sharing, and promote well-informed clinical practice guidelines. Methods— A working group of diverse experts in cerebrovascular clinical trials, epidemiology, and biostatistics met regularly to develop a set of stroke CDEs, selecting among, refining, and adding to existing, field-tested data elements from national registries and funded trials and studies. Candidate elements were revised on the basis of comments from leading national and international neurovascular research organizations and the public. Results— The first iteration of the National Institute of Neurological Disorders and Stroke (NINDS) stroke-specific CDEs comprises 980 data elements spanning 9 content areas: (1) biospecimens and biomarkers; (2) hospital course and acute therapies; (3) imaging; (4) laboratory tests and vital signs; (5) long-term therapies; (6) medical history and prior health status; (7) outcomes and end points; (8) stroke presentation; and (9) stroke types and subtypes. A CDE website provides uniform names and structures for each element, a data dictionary, and template case report forms, using the CDEs. Conclusions— Stroke-specific CDEs are now available as standardized, scientifically vetted, variable structures to facilitate data collection and data sharing in cerebrovascular patient-oriented research. The CDEs are an evolving resource that will be iteratively improved based on investigator use, new technologies, and emerging concepts and research findings.

Common data elements for spinal cord injury clinical research: a National Institute for Neurological Disorders and Stroke project

Objectives:To develop a comprehensive set of common data elements (CDEs), data definitions, case report forms and guidelines for use in spinal cord injury (SCI) clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health.Setting:International Working Groups.Methods:Nine working groups composed of international experts reviewed existing CDEs and instruments, created new elements when needed and provided recommendations for SCI clinical research. The project was carried out in collaboration with and cross-referenced to development of the International Spinal Cord Society (ISCoS) International SCI Data Sets. The recommendations were compiled, subjected to internal review and posted online for external public comment. The final version was reviewed by all working groups and the NINDS CDE team before release.Results:The NINDS SCI CDEs and supporting documents are publically available on the NINDS CDE website and the ISCoS website. The CDEs span the continuum of SCI care and the full range of domains of the International Classification of Functioning, Disability and Health.Conclusion:Widespread use of CDEs can facilitate SCI clinical research and trial design, data sharing and retrospective analyses. Continued international collaboration will enable consistent data collection and reporting, and will help ensure that the data elements are updated, reviewed and broadcast as additional evidence is obtained.

Incorporation of the International Spinal Cord Injury Data Set elements into the National Institute of Neurological Disorders and Stroke Common Data Elements.

Objectives:To develop consistent variable names and a common database structure for the data elements in the International Spinal Cord Injury (SCI) Data Sets.Setting:National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE) Project and The Executive Committee of the International SCI Standards and Data Sets committees (ECSCI).Methods:The NINDS CDE team creates a variable name for each defined data element in the various International SCI Data Sets. Members of the ECSCI review these in an iterative process to make the variable names logical and consistent across the data sets. Following this process, the working group for the particular data set reviews the variable names, and further revisions and adjustments may be made. In addition, a database structure for each data set is developed allowing data to be stored in a uniform way in databases to promote sharing data from different studies.Results:The International SCI Data Sets variable names and database specifications will be available through the web sites of the International Spinal Cord Society (http://www.iscos.org.uk), the American Spinal Injury Association (http://www.asia-spinalinjury.org) and the NINDS CDE project web site (http://www.CommonDataElements.ninds.nih.gov).Conclusion:This process will continue as additional International SCI Data Sets fulfill the requirements of the development and approval process and are ready for implementation.

Standardizing the Structure of Stroke Clinical and Epidemiologic Research Data

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is “to reduce the burden of neurologic disease.” Supporting translational, clinical, and population research in stroke is fundamental to this mission, as stroke is the single greatest nervous system cause of death and disability, both in the United States and worldwide.(1, 2) (3) Accordingly, the NINDS supports a diverse array of translational, clinical trial, epidemiologic, and additional patient-oriented research in cerebrovasular disease, which have had a substantial beneficial effect upon health policy, clinical care, and patient outcomes.(4) However, the fullest potential benefit of these research endeavors has not been realized due to the absence of uniform, widely-accepted formats to characterize demographic, disease, care process, and outcome variables. Data elements are often characterized in varying manners in different studies, hampering cross-study comparisons, recognition of population differences, data-sharing, and pooled analyses. To harmonize data collected across diverse translational, clinical, and population studies, NINDS began the Common Data Element (CDE) Project in 2006.(5) The project aims to standardize naming, definitions, data structure, and response options for all variables commonly employed in NINDS-funded patient and population research. The CDE project complements study-level guidelines from the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network.(6) However, where EQUATOR guidelines focus on the reporting of study level results, the CDE Project focuses on the collection and reporting of individual variable level results, providing guidance for data collection, and facilitating data sharing, at a more granular, patient level. The overall CDE Project has four primary goals: 1) disseminate standards for the collection of data from participants enrolled in studies of neurological diseases; 2) create easily accessible data-collection tools for investigators that are ready to use “off the shelf”; 3) encourage focused and simplified data collection to reduce burden on investigators and practice-based clinicians to increase clinical research participation; and 4) improve study quality and reduce cost of data entry, cleaning and analysis by providing uniform data descriptions and tools across NINDS-funded clinical studies of treatment for neurological diseases.(5, 7) The anticipated benefits of the CDE Project are multiple, and include: 1) rapid and efficient study start-up by allowing investigators access to appropriate data elements, definitions, and case report form templates; 2) improved patient safety by facilitating development of common report templates that can be submitted to oversight committees such as Data and Safety Monitoring Boards (DSMBs); 3) enriched data sharing and data aggregation by employing standard definitions and common forms; and 4) wide adoption of common outcome measures (e.g., functional, cognitive) that may be relevant across the neurological diseases.(5, 7) The CDE Project first developed a set of General CDEs commonly collected in all neuroscience clinical studies, including demographic information, medical history data, medication use, and data needed for safety reporting.(8) Next, development of disease-specific CDEs was undertaken. This paper describes the process and outcome for the development of Stroke CDEs.Background and Purpose— The National Institute of Neurological Disorders and Stroke initiated development of stroke-specific Common Data Elements (CDEs) as part of a project to develop data standards for funded clinical research in all fields of neuroscience. Standardizing data elements in translational, clinical, and population research in cerebrovascular disease could decrease study start-up time, facilitate data sharing, and promote well-informed clinical practice guidelines. Methods— A working group of diverse experts in cerebrovascular clinical trials, epidemiology, and biostatistics met regularly to develop a set of stroke CDEs, selecting among, refining, and adding to existing, field-tested data elements from national registries and funded trials and studies. Candidate elements were revised on the basis of comments from leading national and international neurovascular research organizations and the public. Results— The first iteration of the National Institute of Neurological Disorders and Stroke (NINDS) stroke-specific CDEs comprises 980 data elements spanning 9 content areas: (1) biospecimens and biomarkers; (2) hospital course and acute therapies; (3) imaging; (4) laboratory tests and vital signs; (5) long-term therapies; (6) medical history and prior health status; (7) outcomes and end points; (8) stroke presentation; and (9) stroke types and subtypes. A CDE website provides uniform names and structures for each element, a data dictionary, and template case report forms, using the CDEs. Conclusions— Stroke-specific CDEs are now available as standardized, scientifically vetted, variable structures to facilitate data collection and data sharing in cerebrovascular patient-oriented research. The CDEs are an evolving resource that will be iteratively improved based on investigator use, new technologies, and emerging concepts and research findings.

Improving the value of clinical research through the use of Common Data Elements.

The use of Common Data Elements can facilitate cross-study comparisons, data aggregation, and meta-analyses; simplify training and operations; improve overall efficiency; promote interoperability between different systems; and improve the quality of data collection. A Common Data Element is a combination of a precisely defined question (variable) paired with a specified set of responses to the question that is common to multiple datasets or used across different studies. Common Data Elements, especially when they conform to accepted standards, are identified by research communities from variable sets currently in use or are newly developed to address a designated data need. There are no formal international specifications governing the construction or use of Common Data Elements. Consequently, Common Data Elements tend to be made available by research communities on an empiric basis. Some limitations of Common Data Elements are that there may still be differences across studies in the interpretation and implementation of the Common Data Elements, variable validity in different populations, and inhibition by some existing research practices and the use of legacy data systems. Current National Institutes of Health efforts to support Common Data Element use are linked to the strengthening of National Institutes of Health Data Sharing policies and the investments in data repositories. Initiatives include cross-domain and domain-specific resources, construction of a Common Data Element Portal, and establishment of trans-National Institutes of Health working groups to address technical and implementation topics. The National Institutes of Health is seeking to lower the barriers to Common Data Element use through greater awareness and encourage the culture change necessary for their uptake and use. As National Institutes of Health, other agencies, professional societies, patient registries, and advocacy groups continue efforts to develop and promote the responsible use of Common Data Elements, particularly if linked to accepted data standards and terminologies, continued engagement with and feedback from the research community will remain important.

Common data elements for clinical research in Friedreich's ataxia

To reduce study start‐up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreichs ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups′ recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA.

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

ObjectivesThe common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research.MethodsNine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use.ResultsThe NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website (https://commondataelements.ninds.nih.gov/), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations.ConclusionWe developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.

NINDS Common Data Elements for Congenital Muscular Dystrophy Clinical Research: A National Institute for Neurological Disorders and Stroke Project

BACKGROUND A Congenital Muscular Dystrophy (CMD) Working Group (WG) consisting of international experts reviewed common data elements (CDEs) previously developed for other neuromuscular diseases (NMDs) and made recommendations for all types of studies on CMD. OBJECTIVES To develop a comprehensive set of CDEs, data definitions, case report forms and guidelines for use in CMD clinical research to facilitate interoperability of data collection, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS). METHODS One working group composed of ten experts reviewed existing NINDS CDEs and outcome measures, evaluated the need for new elements, and provided recommendations for CMD clinical research. The recommendations were compiled, internally reviewed by the CMD working group, and posted online for external public comment. The CMD working group and the NIH CDE team reviewed the final version before release. RESULTS The NINDS CMD CDEs and supporting documents are publicly available on the NINDS CDE website (https://www.commondataelements.ninds.nih.gov/CMD.aspx#tab=Data_Standards). Content areas include demographics, social status, health history, physical examination, diagnostic tests, and guidelines for a variety of specific outcomes and endpoints. The CMD CDE WG selected these documents from existing versions that were generated by other disease area working groups. Some documents were tailored to maximize their suitability for the CMD field. CONCLUSIONS Widespread use of CDEs can facilitate CMD clinical research and trial design, data sharing and retrospective analyses. The CDEs that are most relevant to CMD research are like those generated for other NMDs, and CDE documents tailored to CMD are now available to the public. The existence of a single source for these documents facilitates their use in research studies and offers a clear mechanism for the discussion and update of the information as knowledge is gained.