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Astronomical instruments to detect exoplanets require extreme wavefront stability. For these missions to succeed, comprehensive and precise modeling is required to design and analyze suitable coronagraphs and their wavefront control systems. In this paper, we describe techniques for integrated modeling at scale that is, to the best of our knowledge, 1000 times faster than previously published works. We show how this capability has been used to validate performance and perform uncertainty quantification for the Roman Coronagraph instrument. Finally, we show how this modeling capacity may be necessary to design and build the next generation of space-based coronagraph instruments.
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STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To quantify spontaneous upper extremity motor recovery between 6 and 12 months after spinal cord injury (SCI) to help guide timing of nerve transfer surgery to improve upper limb function in cervical SCI. SETTING: Nineteen European SCI rehabilitation centers. METHODS: Data was extracted from the European Multicenter Study of SCI database for individuals with mid-level cervical SCI (N = 268). Muscle function grades at 6 and 12 months post-SCI were categorized for analysis. RESULTS: From 6 to 12 months after SCI, spontaneous surgically-relevant recovery was limited. Of all limbs (N = 263) with grade 0-2 elbow extension at 6 months, 4% regained grade 4-5 and 11% regained grade 3 muscle function at 12 months. Of all limbs (N = 380) with grade 0-2 finger flexion at 6 months, 3% regained grade 4-5 and 5% regained grade 3 muscle function at 12 months. CONCLUSION: This information supports early (6 month) post-injury surgical consultation and evaluation. With this information, individuals with SCI can more fully engage in preference-based decision-making about surgical intervention versus continued rehabilitation and spontaneous recovery to gain elbow extension and/or hand opening and closing.
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Médula Cervical , Transferencia de Nervios , Traumatismos de la Médula Espinal , Médula Cervical/cirugía , Toma de Decisiones , Humanos , Recuperación de la Función/fisiología , Estudios Retrospectivos , Traumatismos de la Médula Espinal/cirugía , Extremidad Superior/cirugíaRESUMEN
PURPOSE: To help individuals make informed choices regarding the optimal type and timing of restorative surgical treatment for cervical spinal cord injury (SCI), more precise information is needed on their ability to perform activities of daily living. The goal of this work was to describe functional independence achieved by individuals with differing levels of cervical SCI. METHODS: Using the comprehensive European Multicenter Study of Spinal Cord Injury dataset, analysis was undertaken of individuals with traumatic SCI, motor-level C5-C8. Data on feeding, bladder management, and transfers (bed to wheelchair) were compared between individuals with different levels of injury. Subgroup analyses of symmetrical and asymmetrical SCI and between complete and incomplete SCI were performed. The impact of age, sex, and time postinjury on functional independence was ascertained. RESULTS: Data were available for individuals with symmetrical (n = 204) and asymmetrical (n = 95) patterns of SCI. Independence with feeding, urinary function, and transfer ability was increased in individuals with strong finger flexion. Unexpectedly, the presence of strong elbow extension did not uniformly result in the ability to transfer independently. There was no change in any of the analyzed activities between 6 and 12 months postinjury. CONCLUSIONS: People with cervical SCI who gain finger flexion have greater independence with feeding, urinary, and transfer activities. Restoration of finger flexion should be a reconstructive priority for individuals with midcervical-level SCI. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.
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Médula Cervical , Traumatismos de la Médula Espinal , Actividades Cotidianas , Estado Funcional , Humanos , Recuperación de la Función , Traumatismos de la Médula Espinal/cirugía , Extremidad Superior/cirugíaRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
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BACKGROUND: Sum scores of ordinal outcomes are common in randomized clinical trials. The approaches routinely employed for assessing treatment effects, such as t-tests or Wilcoxon tests, are not particularly powerful in detecting changes in relevant parameters or lack the ability to incorporate baseline information. Hence, tailored statistical methods are needed for the analysis of ordinal outcomes in clinical research. METHODS: We propose baseline-adjusted proportional odds logistic regression models to overcome previous limitations in the analysis of ordinal outcomes in randomized clinical trials. For the validation of our method, we focus on common ordinal sum score outcomes of neurological clinical trials such as the upper extremity motor score, the spinal cord independence measure, and the self-care subscore of the latter. We compare the statistical power of our models to other conventional approaches in a large simulation study of two-arm randomized clinical trials based on data from the European Multicenter Study about Spinal Cord Injury (EMSCI, ClinicalTrials.gov Identifier: NCT01571531). We also use the new method as an alternative analysis of the historical Sygen®clinical trial. RESULTS: The simulation study of all postulated trial settings demonstrated that the statistical power of the novel method was greater than that of conventional methods. Baseline adjustments were more suited for the analysis of the upper extremity motor score compared to the spinal cord independence measure and its self-care subscore. CONCLUSIONS: The proposed baseline-adjusted proportional odds models allow the global treatment effect to be directly interpreted. This clear interpretation, the superior statistical power compared to the conventional analysis approaches, and the availability of open-source software support the application of this novel method for the analysis of ordinal outcomes of future clinical trials.
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Traumatismos de la Médula Espinal , Humanos , Modelos Logísticos , Autocuidado , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/terapiaRESUMEN
STUDY DESIGN: Narrative review. PURPOSE: To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI). RESULTS: With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified. CONCLUSION: Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.
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Traumatismos de la Médula Espinal , Sistema Nervioso Central , Humanos , Sistema de Registros , Proyectos de Investigación , Traumatismos de la Médula Espinal/terapiaRESUMEN
STUDY DESIGN: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI). OBJECTIVES: To identify key problems of recruitment and explore potential approaches to overcoming them. METHODS: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors. RESULTS: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies. CONCLUSIONS: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.
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Ensayos Clínicos como Asunto/métodos , Selección de Paciente , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/terapia , Humanos , Traumatismos de la Médula Espinal/diagnósticoRESUMEN
STUDY DESIGN: This is a focused review article. OBJECTIVES: To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. METHODS: This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. RESULTS: There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. CONCLUSION: There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.
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Ensayos Clínicos como Asunto/métodos , Extremidad Inferior/fisiopatología , Evaluación de Resultado en la Atención de Salud , Traumatismos de la Médula Espinal/terapia , Humanos , Traumatismos de la Médula Espinal/patologíaRESUMEN
OBJECTIVES: To describe the process and outcomes of using a new evidence base to develop scientific guidelines that specify the type and minimum dose of exercise necessary to improve fitness and cardiometabolic health in adults with spinal cord injury (SCI). SETTING: International. METHODS: Using Appraisal of Guidelines, Research and Evaluation (AGREE) II reporting criteria, steps included (a) determining the guidelines' scope; (b) conducting a systematic review of relevant literature; (c) holding three consensus panel meetings (European, Canadian and International) to formulate the guidelines; (d) obtaining stakeholder feedback; and (e) process evaluation by an AGREE II consultant. Stakeholders were actively involved in steps (c) and (d). RESULTS: For cardiorespiratory fitness and muscle strength benefits, adults with a SCI should engage in at least 20 min of moderate to vigorous intensity aerobic exercise 2 times per week AND 3 sets of strength exercises for each major functioning muscle group, at a moderate to vigorous intensity, 2 times per week (strong recommendation). For cardiometabolic health benefits, adults with a SCI are suggested to engage in at least 30 min of moderate to vigorous intensity aerobic exercise 3 times per week (conditional recommendation). CONCLUSIONS: Through a systematic, rigorous, and participatory process involving international scientists and stakeholders, a new exercise guideline was formulated for cardiometabolic health benefits. A previously published SCI guideline was endorsed for achieving fitness benefits. These guidelines represent an important step toward international harmonization of exercise guidelines for adults with SCI, and a foundation for developing exercise policies and programs for people with SCI around the world.
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Medicina Basada en la Evidencia/normas , Terapia por Ejercicio/normas , Guías de Práctica Clínica como Asunto/normas , Traumatismos de la Médula Espinal/rehabilitación , Adulto , Capacidad Cardiovascular/fisiología , Terapia por Ejercicio/métodos , Humanos , Cooperación InternacionalRESUMEN
Authors Victoria L. Goosey-Tolfrey and Karen M. Smith were listed under the incorrect affiliations at the time of publication.
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STUDY DESIGN: This is a focused review article. OBJECTIVES: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified. METHODS: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review. RESULTS: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered. CONCLUSIONS: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.
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Ensayos Clínicos como Asunto/métodos , Evaluación de Resultado en la Atención de Salud/métodos , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/terapia , HumanosRESUMEN
BACKGROUND: A number of potential therapeutic approaches for neurological disorders have failed to provide convincing evidence of efficacy, prompting pharmaceutical and health companies to discontinue their involvement in drug development. Limitations in the statistical analysis of complex endpoints have very likely had a negative impact on the translational process. METHODS: We propose a transitional ordinal model with an autoregressive component to overcome previous limitations in the analysis of Upper Extremity Motor Scores, a relevant endpoint in the field of Spinal Cord Injury. Statistical power and clinical interpretation of estimated treatment effects of the proposed model were compared to routinely employed approaches in a large simulation study of two-arm randomized clinical trials. A revisitation of a key historical trial provides further comparison between the different analysis approaches. RESULTS: The proposed model outperformed all other approaches in virtually all simulation settings, achieving on average 14 % higher statistical power than the respective second-best performing approach (range: -1 %, +34 %). Only the transitional model allows treatment effect estimates to be interpreted as conditional odds ratios, providing clear interpretation and visualization. CONCLUSION: The proposed model takes into account the complex ordinal nature of the endpoint under investigation and explicitly accounts for relevant prognostic factors such as lesion level and baseline information. Superior statistical power, combined with clear clinical interpretation of estimated treatment effects and widespread availability in commercial software, are strong arguments for clinicians and trial scientists to adopt, and further extend, the proposed approach.
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Traumatismos de la Médula Espinal/diagnóstico , Brazo/fisiopatología , Ensayos Clínicos como Asunto , Humanos , Análisis Multivariante , Fuerza Muscular , Recuperación de la Función , Análisis de Regresión , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Resultado del TratamientoRESUMEN
CONTEXT/OBJECTIVE: To assess short-term changes in health outcomes in people with cervical-level spinal cord injury (SCI) who underwent upper extremity (UE) reconstruction via either novel nerve transfer (NT) or traditional tendon transfer (TT) surgery with individuals who did not undergo UE surgical reconstruction. DESIGN: Prospective, comparative cohort pilot study. PARTICIPANTS: 34 participants with cervical SCI met the following inclusion criteria: age 18 or older, greater than 6 months post-injury, and mid-cervical level SCI American Spinal Injury Association Impairment Scale (AIS) A, B or C. SETTING: Two tertiary academic hospitals and their affiliated veterans' hospitals. METHODS: Health outcomes were assessed using two previously validated measures, the Spinal Cord Independence Measure (SCIM) and Short-Form Health Survey (SF-36). Demographic, surgical, and survey data were collected at the initial evaluation and one month postoperatively/post-baseline. RESULTS: 34 participants with cervical SCI were recruited across three cohorts: no surgery (n = 16), NT (n = 10), and TT (n = 8). The TT group had a decline in SCIM and SF-36 scores whereas the NT and no surgery groups experienced little change in independence or health status in the immediate perioperative period. CONCLUSIONS: Surgeons and rehabilitation providers must recognize differences in the perioperative needs of people with cervical SCI who chose to have restorative UE surgery. Future work should focus on further investigation of health outcomes, change in function, and improving preoperative counseling and cross-disciplinary management.
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BACKGROUND: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories. OBJECTIVES: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups. METHODS: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function. RESULTS: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids). CONCLUSION: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice.
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Enfermedades del Sistema Nervioso , Traumatismos de la Médula Espinal , Humanos , Paraplejía , Caminata/fisiología , Pronóstico , Recuperación de la FunciónRESUMEN
OBJECTIVE: To assess how frequently subjects with spinal cord injuries (SCIs) classified as American Spinal Injury Association Impairment Scale (AIS) grade A have substantial preserved motor function below the neurologic level of injury, despite having no preserved sensory or motor function at the S4-5 spinal cord segment. DESIGN: Analysis of the European Multicenter Study about Spinal Cord Injury database to determine how frequently subjects assessed as AIS A would have been AIS D based on motor scores alone (ie, had scores of ≥3 in at least half of the International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] key muscles below the neurologic level of injury, despite having no sacral sparing). SETTING: Eighteen European centers. PARTICIPANTS: Individuals with traumatic SCI at any level (total of 2557 assessments). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: ISNCSCI assessments. RESULTS: Over the first year after SCI (with assessments at approximately 1, 4, 12, 24, and 48wk) and for all rostrocaudal levels of injury, only 3.2% of AIS A assessments were found to meet the AIS D motor score criteria. The percentage was highest for lumbar (16.3%) and lower thoracic (4.4%) SCI. No trends were observed across time points. CONCLUSIONS: These results suggest that the low frequency of individuals with an AIS A classification and high levels of motor function are not a significant concern in subject recruitment for clinical trials, unless the level of SCI is within the lumbar cord.
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Movimiento , Traumatismos de la Médula Espinal/clasificación , Traumatismos de la Médula Espinal/fisiopatología , Vías Aferentes/fisiopatología , Vértebras Cervicales , Vías Eferentes/fisiopatología , Humanos , Vértebras Lumbares , Ensayos Clínicos Controlados Aleatorios como Asunto , Vértebras Torácicas , Índices de Gravedad del TraumaRESUMEN
BACKGROUND/OBJECTIVES: In order to guide and improve rehabilitation interventions for grip function after spinal cord injury (SCI), it is important to have a detailed understanding of the motor control strategies that the central nervous system uses to control the hand. We examined whether changes in the motor control of the hand after SCI are manifested in the form of changes to muscle synergies. We further sought to determine a correlation between functional ability and the extent of muscle synergy disruption. METHODS: Surface electromyographic (EMG) data were recorded from 8 hand muscles in 10 able-bodied subjects and 6 subjects with SCI as they performed various functional tasks using grip types relevant to activities of daily living. Muscle synergies were extracted using non-negative matrix factorization. Functional performance in each task was quantified using a 5-point clinical scale. RESULTS: The synergies most commonly observed in able-bodied subjects were co-activation of extensor digitorum communis and extensor indicis proprius, as well as of flexor digitorum superficialis with flexor carpi ulnaris. The proportion of subjects in which particular synergies occurred was significantly different for subjects with SCI compared to able-bodied subjects (P < 0.001). Deviations from the average able-bodied synergies in subject with SCI were found to be poorly correlated (r = -0.04) with functional ability. CONCLUSIONS: Results suggest that the disruptions and re-organizations of neural circuitry after SCI are reflected by the extracted muscle synergies, but the question of how muscle synergies can guide rehabilitation interventions remains open.
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Vías Eferentes/fisiología , Mano/fisiología , Músculo Esquelético/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/rehabilitación , Actividades Cotidianas , Adulto , Anciano , Electromiografía , Mano/inervación , Fuerza de la Mano/fisiología , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiologíaRESUMEN
The principles of spinal cord injury clinical trial programs are briefly reviewed as one example of the challenge faced by most human studies of neurologically directed therapeutic interventions, including rehabilitation strategies. Different trial protocols are reviewed, as are inclusion/exclusion criteria for study subjects, the choice of clinical endpoints, and the statistical approaches that might be used in a trial program. Potential factors that might confound the accurate interpretation of trial data are also identified. Regardless of the specific therapeutic target or the rehabilitation strategy to be evaluated, there are many unresolved issues that will have to be answered before specific and effective prescriptions can be delivered.
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BACKGROUND: New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations. OBJECTIVE: Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria. METHODS: Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury. RESULTS: URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients. CONCLUSION: URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.