Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia

Jessica E Morgan
Lesley Stewart
Robert S Phillips
Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia
P R O T O C O L Open Access
Background: Febrile neutropenia is a common complication of therapy in children with cancer. Some patients are at low risk of complications, and research has considered reduction in therapy for these patients. A previous systematic review broadly considered whether outpatient treatment and oral antibiotics were safe in this context and concluded that this was likely to be the case. Since that review, there has been further research in this area. Therefore, we aim to provide a more robust answer to these questions and to additionally explore whether the exact timing of discharge, including entirely outpatient treatment, has an impact on outcomes. Methods/design: The search will cover MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CDSR, CENTRAL, LILACS, HTA and DARE. A full search strategy is provided. Key conference proceedings and reference lists of included papers will be hand searched. Prominent authors/clinicians in the field will be contacted. We will include randomised and quasi-randomised controlled trials along with prospective single-arm studies that examine the location of therapy and/or the route of administration of antibiotics in children or young adults (aged less than 18 years) who attend paediatric services with fever and neutropenia due to treatment for cancer and are assessed to be at low risk of medical complications. Studies will be screened and data extracted by one researcher and independently checked by a second. All studies will be critically appraised using tools appropriate to the study design. Data from randomised controlled trials (RCTs) will be combined to provide comparative estimates of treatment failure, safety and adequacy. Information from quasi-randomised trials and single-arm studies will provide further data on the safety and adequacy of regimes. Random effects meta-analysis will be used to combine studies. A detailed analysis plan, including assessment of heterogeneity and publication bias, is provided. Discussion: This study will aim to specifically define the features of a low-risk strategy that will maintain levels of safety and adequacy equivalent to those of traditional treatments. This will both inform the development of services and provide patients and families with data to help them make an informed decision about care. Systematic review registration: PROSPERO CRD42014005817

Background

Febrile neutropenia describes the presence of fever, representing infection, in a patient who has poor immunity due to low neutrophils. It is the commonest life-threatening complication of treatment of children with cancer [1]. It occurs in around a third of episodes of neutropenia, at a rate of 0.75 episodes per 30 days at risk [2]. A large number of patients with febrile neutropenia have no significant sequelae of the condition, whilst a smaller number are at high risk of medical complications including organ failure and death.

Standard care in the UK usually involves intravenous (IV) antibiotics and at least 48 h as an inpatient [3]. However, research has begun to focus on whether treatment can be reduced safely for those patients who are considered to be at low risk of complications of febrile neutropenia [1]. This may provide benefits of improved quality of life, reduction in hospital-acquired infection, cost savings and reduced pressures on the health service [4][5][6][7]. However, any reduction in therapy must be both safe and effective to justify a change from current practice.

A previous systematic review compared two aspects of the reduction of therapy [8]. It compared outpatient treatment with inpatient treatment, and oral antibiotics with IV therapy. It included only low-risk patients as defined by individual study protocols, recognising that this is a heterogeneous group.

The review found that treatment failure was as likely to occur in inpatients compared with outpatients and that inpatients were more likely to have alterations made to their antibiotic regimes. Within the studies included, two low-risk patients died-they had both been treated as inpatients. They found no increase in medical complications with oral therapy. In particular, there were no deaths on oral therapy, and no increase in readmission to hospital or in treatment failure, including the need to modify the antibiotic regime.

Although this provided essential information about the broad concepts of outpatient and oral therapy for febrile neutropenia, it involved combining data from very different groups and thus lost some of the nuanced information from original trials. This is particularly important when considering timing of discharge as further information is required to know precisely when discharge should be advised. Furthermore, the review was restrictive in its search strategy, excluding non-English language papers, using few databases and having no grey literature searching. In addition to these limitations, important further work has since emerged in this area. In particular, one trial looked specifically at early step-down from intravenous antibiotics given as an inpatient to oral outpatient treatment within 22 h of presentation with febrile neutropenia [9].

Meanwhile, a recent Cochrane review looking at both adult and paediatric patients with febrile neutropenia found that oral therapy was an acceptable alternative to intravenous [10]. A subgroup analysis of paediatric studies found no difference in treatment failure rates within this population, although this included exclusively randomised controlled trials, of which there were only eight identified in children. Furthermore, it did not examine specifically the issue of location of treatment. Our systematic review, which will also include studies using observational methods, aims to provide further depth and clarity to these findings.

Given all of these issues and the high likelihood of other new and relevant studies, we decided that a new systematic review should be performed. Our review will have more focused aims, particularly in defining the most appropriate time of discharge in these patients, and will have a new and more thorough search strategy.

Aims, objectives and overview of approach

This systematic review aims to provide an up-to-date and robust assessment of the role of the route of antibiotic administration and the location of treatment in the management of low-risk febrile neutropenia in children being treated for cancer. We will aim to define the overall success (or failure) of each treatment regime in resolving an episode of febrile neutropenia without complications. Furthermore, we intend to explore the main two components of this overall impression-that is safety and efficacy-for each potential regime. In particular, we will explore the timing of discharge (before 24 h, 24-48 h or after 48 h), including the role of entirely outpatient treatment. This will provide more detailed information about how lowrisk services might be designed.

Finally, we understand that there may be concern regarding reduction of therapy from patients, their parents and the healthcare professionals caring for them. This systematic review will therefore collect data on rates of declined consent, where this has been reported, as a way of gaining insight into the potential acceptability of these approaches.

Methods/design

This systematic review will be undertaken following guidelines from Cochrane [11] and CRD [12].

Search and retrieval strategy

The search strategy focuses on febrile neutropenia and the interventions of antibiotics and early discharge, with a paediatric filter (see Additional file 1: Appendix 1). The antibiotic search terms were the same as those used in the development of the NICE clinical guideline for neutropenic sepsis and reflect the antibiotics that have been commonly used to treat febrile neutropenia, either previously or currently, within the UK [13].

The following electronic sources will be searched: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CDSR, CENTRAL (via the Cochrane Library), LILACS, HTA and DARE. The full MEDLINE search strategies are included in Additional file 1: Appendix 1.

Conference proceedings of the RCPCH (Royal College of Paediatrics and Child Health), SIOP (International Society of Paediatric Oncology), ASPHO (American Society of Pediatric Hematology/Oncology), ASCO (American Society of Clinical Oncology) and ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy) meetings will be hand searched for relevant abstracts. Reference lists of relevant systematic reviews and included articles will also be reviewed.

Authors of relevant studies and prominent clinicians within the field will be contacted as time allows seeking further studies, as this is likely to be a poorly indexed area of biomedical research (see Additional file 1: Appendix 2).

Published and unpublished studies will be sought and no language restrictions applied. The latter is important because we suspect that there may be a number of studies that have been performed in Spain, Portugal and South America as these areas have active research in paediatric oncology. Non-English language studies will be translated if this is possible within 3 months of running the searches. This time limit will ensure that the results of this review are available to inform further aspects of an overarching multi-methods PhD project.

Screening for eligibility

One reviewer will screen the title and abstract of all studies for inclusion. A second reviewer will independently screen a sample of 1,000 papers or 10% of those identified through the search, whichever is greater. The kappa statistic for agreement will be calculated, and if this shows significant disagreement (κ <0.4), all other titles and abstracts will be screened by a second reviewer. Where it is not possible to identify whether a study should be included from the title and abstract, then the full text of the paper will be sought and then assessed using the study eligibility form (see Additional file 1: Appendix 3). All full-text assessments will be performed by two reviewers. Disagreements regarding which studies to include will be resolved by consensus or, if this proves impossible, by recourse to an independent adjudicator.

Inclusion and exclusion criteria

Studies will be included in the review if they meet the following criteria:

Study design

Outcomes of interest will be explored using both comparative and non-comparative data. Randomised controlled trials (RCTs) will provide the most reliable evidence on effectiveness and will also aim to give clarity on the role of timing of discharge in safety and adequacy. However, we anticipate that the number of RCTs in this area will be small.

Furthermore, there is benefit in knowing the absolute numbers of patients experiencing failures in safety and adequacy when treated with oral antibiotics on an outpatient basis. This can be obtained using non-comparative data from both single-arm studies and the separate arms of RCTs.

We will include RCTs and prospective single-arm studies. Quasi-randomised trials will be eligible for inclusion provided the methods of allocation to treatment groups are clearly described. Randomised controlled trials will be used for comparative analyses. Quasi-randomised trials will be analysed separately, but where they are assessed to be similar to the RCTs then the two groups will be combined. Where this combination is performed, this will be clearly stated in the report. Individual arms of the trials and prospective single-arm studies will be used for the non-comparative analyses.

Retrospective studies will be excluded. Studies that enrolled participants ≥24 h after initial empiric treatment will be excluded.

Population

The population will include children or young adults (aged less than 18 years) who attend paediatric services with fever and neutropenia secondary to treatment for cancer and who are assessed to be at low risk of medical complications.

We will include studies that enrolled only children. Studies in which the majority (defined as >80%) of patients are less than 18 years old will be included, even if those patients are not reported separately. This reflects the fact that some paediatric studies may include a small number of young adults who have malignancies and physiology similar to the paediatric cohort being investigated and who are therefore treated within teenage and young adult services by paediatricians. Such studies designed for the paediatric group that have recruited small numbers of young adults do not generally recruit from the older adult population, in which the causes and outcomes of febrile neutropenia are likely to be different. Studies of adults which report data for patients less than 18 years old will be included, if outcome data for children are reported separately. Studies which include >20% of adult populations and those which include mixed age populations with no details on age distribution will be excluded.

To be included, details of the risk stratification rule used must be available, but there will be no eligibility restriction concerning the definitions of fever and neutropenia or the stratification rule used. These are likely to vary across studies reflecting variations in current clinical practice [6]. Studies of multiple risk groups will be included, if data for low-risk patients (as defined by study protocols) can be extracted separately.

Interventions and comparators

We are aware that studies have included a variety of treatment regimes, including inpatient IV therapy, outpatient IV therapy and oral outpatient therapy [8]. This creates a challenge as there are two components to the comparison-the route of administration of the antibiotics (IV or oral) and the location of the patient's treatment (outpatient or inpatient)-which could be correlated in individual studies. In particular, oral antibiotics and outpatient treatment are likely to be used together and it may be difficult to establish whether any differences in outcome are related to the route, the location of treatment or both. The considerable intermeshing of these two issues within the literature justifies the use of a single review to attempt to address the various options in reduction of therapy to these patients.

Prospective single-arm studies must examine the features of route of administration and/or location of treatment as the primary aim of the study. We anticipate that these studies will therefore describe oral therapy and/or outpatient location. Studies examining different antibiotics given by the same route and in the same location will be excluded.

To be included, a study must have investigated for one or more of the following interventions:

We will include studies that compare outpatient with inpatient (less than 8 h in hospital) care. The location of treatment may change at any point during the episode of febrile neutropenia, but the time of change must be clearly reported. Justification for using an 8-h cut-off is a practical one. The time taken to review a patient, ensure they are eligible for outpatient treatment and then prescribe and obtain any medications to take home may be up to 8 h. Any period longer than this could reasonably be called admission to hospital. (ii)Route of antibiotic administration:

We will include studies that compare oral with IV antibiotics. The route of administration may change at any point during the episode of febrile neutropenia but the time of change must be clearly reported.

Where patients receive a single dose of IV antibiotics followed by a course of oral antibiotics, this will be considered to be an entirely oral course. This is to allow for studies in which IV antibiotics are administered whilst awaiting the results of blood tests to confirm low risk status, but once the patient is identified as low risk, they are started on oral antibiotics. The sheer variety in the antibiotics used for paediatric febrile neutropenia will add complexity. Both the previous review by Manji et al. and the recent NICE guideline found numerous different antibiotic regimes studied, in both adult and paediatric protocols [8,14]. It is worth noting however that although the specific antibiotics used are varied, the coverage of these antibiotics is certainly less so. Thus, differences between regimes are more likely to be related to the route of administration, including absorption and dosing, than the specific antibiotic used.

Outcomes

There will be three primary outcomes in this review: treatment failure, safety and adequacy. Treatment failure is a composite outcome for various reasons. Firstly, this is in line with multinational guidelines which have recommended that the primary outcome of studies into febrile neutropenia should be such a composite measure [15]. The rationale for this approach is that this is likely to be the information that patients and clinicians combine when making decisions about choice of care; thus, it is the most clinically relevant outcome for those involved in paediatric haematology and oncology services. In addition, from a practical point of view, the studies which are likely to be included have generally reported composite outcomes, rather than individual medical complications [16]. We will also address two important parts of this composite outcome separately. This is because each informs separate aspects of service transformation and because different sources of evidence will be considered for each (primarily because anticipated low numbers of adverse events mean that we will need to look beyond comparative studies). Exploration of safety will consider the frequency of medical complications, in particular admissions to critical care services or death. Adequacy will relate to the ability of a treatment protocol to result in resolution of the episode of febrile neutropenia, without change in antibiotic or location of the patient. Although these outcomes might be seen as different ways of measuring a similar problem, from a clinical point of view, they are important for different reasons. Knowledge about the safety of a strategy is essential to be able to consider its use at all, whilst adequacy allows services to plan appropriately for potential readmissions or changes in treatment associated with changing to a new low-risk strategy.

To be included, a study must have recorded and data be available for one or more of the following outcomes:

Primary outcomes

1. Treatment failure at 30 days. This will include persistence, worsening or recurrence of fever/infecting organisms, new infections, readmission, admission to critical care services or death during treatment. For the primary outcome, modification of antibiotics will also indicate treatment failure. We acknowledge that each study is unlikely to select an outcome that completely fits the definition given above. Therefore, the composite outcome that each individual study selects will be recorded within the data collection stage of this systematic review. The selection of 30 days as a cut-off for this outcome is for both clinical and practical reasons. Clinically, most periods of neutropenia last for less than 30 days and, indeed, most chemotherapy regimes are based on cycles of around 3 weeks for this reason. Thus, individual episodes of febrile neutropenia are generally limited within this time frame. Related to this, and on a more practical note, studies in the area of febrile neutropenia usually report outcomes at 28 to 30 days. 2. Safety: number of medical complications, defined as admissions to critical care services or death. 3. Adequacy: ability of a treatment protocol to result in resolution of the episode of febrile neutropenia, without change in antibiotic or location of the patient.

Secondary outcomes

The secondary outcomes will include treatment failure with modification of antibiotics excluded, time spent in hospital, adverse events leading to antibiotic discontinuation, 30-day overall mortality and infection-related mortality and the individual components of the primary composite outcome.

Data extraction and assessment of risk of bias

Data will be extracted by one researcher using a standardised data extraction form (see Additional file 1: Appendix 4) and independently checked by a second. If the data to be extracted is unclear, authors will be contacted for further information. If there is no response, a further attempt to make contact will be made a fortnight later. If there is no response after a further 4 weeks, the data will be presumed unavailable. The risk of bias in each study will be assessed using an appropriate tool, dependent on the design of the original study (see Additional file 1: Appendix 5). Assessment of randomised controlled trials will be based on the Cochrane risk of bias [11]. Single-arm studies will be assessed using the tool written by Hayden and used by NICE for prognostic studies [17].

Methods of analysis/synthesis

The study characteristics and quality assessments will be described narratively and represented in tabular form. A full list of anticipated statistical analyses can be found in Additional file 1: Appendix 6. Any post hoc analyses performed outwith those defined in this protocol will be clearly identified as such in the presentation of results.

(1)Comparative analysis Randomised controlled trials and quasi-randomised trials will be analysed as separate groups. These will be combined if they include similar patients and methods, so as to give an estimate of effect in all studies.

Interventions will be analysed separately by location of treatment and by route of antibiotic administration.

Odds ratios will be calculated for treatment failure at 30 days, safety and adequacy for each individual study, assessing the route of antibiotic administration and location of treatment separately. These odds ratios will then be combined using a random effects model, given the anticipated clinical heterogeneity. Forest plots will be presented for each outcome.

Weighted mean differences will be calculated for rates of treatment failure, safety and adequacy of both oral antibiotics compared with IV, and outpatient compared with inpatient treatment.

Results will be expressed in both relative (odds ratios) and absolute terms (weighted mean difference). (2)Wider exploration of safety and adequacy Safety and adequacy outcomes will be explored using data derived from single-arm studies and from the individual arms of comparative studies. Weighted averages for treatment failure, safety and adequacy of different routes of administration and locations of treatment will be reported separately.

A weighted average of the readmission rate in outpatient treatment arms will also be calculated.

(3)Exploration of consent to randomisation

We will use the data from all included studies (RCTS, prospective cohorts and prospective single-arm studies) combined using a random effects model to report a weighted average of declining to consent for reduction in therapy studies.

Heterogeneity

Heterogeneity will be examined by visual inspection of forest plots and using the chi-squared test of heterogeneity (recognising that this test has low power in metaanalyses of multiple small studies which this systematic review is likely to include). The I 2 test will be used to quantify the degree of heterogeneity that is not due to chance. The tau 2 statistic will be calculated to assess the between-study variance of true effect.

Subgroup analyses Time of discharge

Studies will be grouped according to their definition of early discharge to explore whether the benefits and risks of early discharge are affected by different time periods before 24 h, 24-48 h, after 48 h.

These time periods were selected as they represent the frequency of medical ward rounds, at which the patient is most likely to be reviewed and potentially discharged. Assessing these time points may provide particularly salient clinical information as to a specific point at which consideration of early discharge might be most appropriate. Where studies provide a range of times at which early discharge might be considered, for example 8 to 22 h as in the SPOG study, the earliest time at which discharge could be considered will be the time used to categorise the study [9].

Risk stratification tool

There are a large number of different risk stratification tools in current use (25 in the most up-to-date systematic review) which creates a potential source of clinical difference between studies [18]. For those rules that have been considered in more than one study, studies will be grouped by the specific risk stratification tool used and subgroup analysis performed.

Time of risk assessment

The time at which the risk assessment is made may affect which patients are eligible to be discharged and may affect results from the study. When risk assessment is performed later in the episode of febrile neutropenia, for example at 24 h rather than at admission, then more information is likely to be available for this assessment, such that the risk of misclassifying a patient as low risk when they are in fact high risk is reduced. Therefore, the outcomes for patients in whom the risk assessment is performed later may be better than those who are risk stratified at presentation. This hypothesis will also be assessed by subgroup analysis.

Risk stratified within 8 h of presentation Risk stratified between 8 and 24 h Risk stratified after 24 h

Sensitivity analyses

Potential areas of heterogeneity that will be explored using sensitivity analyses include the inclusion/exclusion of studies reported as conference abstracts, restricting comparative analyses to randomised controlled trials only, risk of bias assessed by components (particularly selection and attrition bias), the use of fixed effects rather than random effects meta-analysis, definitions of fever and neutropenia used by the study, the definition of treatment failure used by the study, the specific antibiotics used in each arm of the studies, and the location of the study, which provides information on both standards of care and the likely micro-organisms involved in febrile neutropenia.

Publication bias

Publication bias within this area may be relatively high, given that studies in children and young people are often small and may be difficult to recruit into. These studies are more likely to produce non-significant results and are thus at risk of positive result and time lag biases [19]. However, these studies may be of greatest interest in this particular research question.

In recognition of this, along with thorough searching, the data analysis phase will explore the risk of publication bias. A contour-enhanced funnel plot will be created for each primary outcome, showing the value for each study (i.e. the rate of treatment failure, medical complications or efficacious treatment) plotted against sample size. Formal statistical testing for publication bias will be performed using Harbord and Peters tests, as the primary outcome is binary. Any potential bias will be investigated with a cumulative forest plot to identify the impact of smaller studies on the results.

Methods of dissemination

The results of this review will be written for publication in a scholarly journal following the PRISMA reporting guidelines as closely as possible [20]. Areas of uncertainty and suggestions for further research will be outlined within the final report. Lay and professional summaries of the project will also be produced and be available on the CRD's website. The lay summary will be offered for inclusion in the newsletter produced by Candlelighters, the children's cancer charity that is supporting this work.

Discussion

This study will aim to specifically define the features of a low-risk strategy for paediatric febrile neutropenia that will maintain levels of safety and adequacy equivalent to those of traditional treatments. This will both inform the development of services and provide patients and families with data to help them make an informed decision about care.

Additional file

Additional file 1: Appendix 1: Search strategy. Appendix 2: Email to elicit unpublished studies. Appendix 3: Study eligibility decision form. Appendix 4: Data extraction tool. Appendix 5: Assessment of risk of bias. Appendix 6: Anticipated statistical analyses. and revise the protocol. LS helped to inform the study design and revise the manuscript. All authors read and approved the final protocol.
 http://www.systematicreviewsjournal.com/content/3/1/119
AcknowledgementsWe thank Kate Lewis-Light, Centre for Reviews and Dissemination, University of York, information scientist, for assisting in the development, testing and translation of the search strategies. We would also like to thank Candlelighters Children's Cancer Charity (Registered Charity No 1045077) who have provided funding for JM's work on this project.AbbreviationsIV: intravenous; NICE: National Institute for Health and Care Excellence; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SPOG: Swiss Paediatric Oncology Group.Competing interestsThe authors declare that they have no competing interests.Authors' contributions JM designed the study in collaboration with other authors and obtained funding for it as part of her PhD fellowship. She developed the search strategies in collaboration with an information specialist and registered and drafted the protocol. She will coordinate the study and act as the principal reviewer. RP conceived the study and helped to inform the study design
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Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia. Morgan, Systematic Reviews. 3119Cite this article asCite this article as: Morgan et al.: Protocol for a systematic review of reductions in therapy for children with low-risk febrile neutropenia. Systematic Reviews 2014 3:119.


Recommendations to Improve Downloads of Large Earth Observation Data
2018

Rahul Ramachandran email@example.com
NASA Marshall Space Flight Center
US

Christopher Lynnes
Kathleen Baynes
Kevin Murphy
Jamie Baker
Jamie Kinney
Ariel Gold
Jed Sundwall
Mark Korver
Allison Lieber
William Vambenepe
Matthew Hancher
Rebecca Moore
Tyler Erickson
Josh Henretig
Brant Zwiefel
Heather Patrick-Ahlstrom
Matthew J Smith
Rahul Ramachandran

CODATA CODATA I I S S U U Ramachandran

Recommendations to Improve Downloads of Large Earth Observation Data

Data Science Journal
172201810.5334/dsj-2018-002PRACTICE PAPER 2 NASA Goddard Space Flight Center, US 3 NASA Headquarters, US 4 Amazon Web Services, US 5 Google, US 6 Microsoft, US Corresponding author:Earth Observation DataLarge Data TransfersCloudBest Practices
With the volume of Earth observation data expanding rapidly, cloud computing is quickly changing the way these data are processed, analyzed, and visualized. Collocating freely available Earth observation data on a cloud computing infrastructure may create opportunities unforeseen by the original data provider for innovation and value-added data re-use, but existing systems at data centers are not designed for supporting requests for large data transfers. A lack of common methodology necessitates that each data center handle such requests from different cloud vendors differently. Guidelines are needed to support enabling all cloud vendors to utilize a common methodology for bulk-downloading data from data centers, thus preventing the providers from building custom capabilities to meet the needs of individual vendors. This paper presents recommendations distilled from use cases provided by three cloud vendors (Amazon, Google, and Microsoft) and are based on the vendors' interactions with data systems at different Federal agencies and organizations. These specific recommendations range from obvious steps for improving data usability (such as ensuring the use of standard data formats and commonly supported projections) to non-obvious undertakings important for enabling bulk data downloads at scale. These recommendations can be used to evaluate and improve existing data systems for high-volume data transfers, and their adoption can lead to cloud vendors utilizing a common methodology.

Introduction

Purpose

With the volume of Earth observation data expanding rapidly, cloud computing is quickly changing the way these data are processed, analyzed, and visualized. The cloud infrastructure provides the flexibility to scale up (for both storage and computation) to large volumes of data and to efficiently process high velocity data streams. Collocating freely available Earth observation data on a cloud infrastructure may create opportunities for innovation and value-added data re-use that were unforeseen by the original data provider (or data center). These innovations could spur new industries and applications and spawn scientific pathways previously undiscoverable due to data volume and computational infrastructure limitations. Various cloud vendors are now regularly accessing data from multiple data centers, and they can be viewed as a new class of data consumer, with distinct search, access, and use patterns which differentiate them from researchers (the typical data users).

NASA, in collaboration with Amazon, Google, and Microsoft, propose a set of recommendations to enable efficient transfer of Earth observation data from existing data systems to a cloud computing infrastructure. The purpose of these recommendations is to guide all data providers in evaluating existing data systems and improving any issues uncovered to enable efficient search, access, and use of large volumes of data. Employing these recommendations as an integrated set of guidelines can allow cloud vendors to utilize a common methodology for bulk-downloading data from data providers, thus preventing the providers from building custom capabilities to meet the needs of individual vendors. The adoption of these recommendations as a set of guidelines will benefit a new class of data consumer interested in moving large volumes of data from a data center to any other location. In the remainder of the paper, the term "user" refers to this new class of data consumer, namely cloud vendors who want to provide data as a resource to their customers but also applies to researchers needing to leverage cloud computing or any distributed high-performance computing environment.

Scope

Barriers to data acquisition as well as technical challenges prevent data from being utilized to their full potential (Overpeck, et al., 2011). In order to reduce these challenges, the U.S. Group on Earth Observations (USGEO) drafted the Common Framework for Earth-Observation Data, which provides Federal agencies with recommended standards on various facets of data management (National Science and Technology Council Committee on Environment, Natural Resources, and Sustainability, U.S. Group on Earth Observations Subcommittee Data Management Working, 2016). These data management facets include data search and discovery services, data access services, data documentation, and compatible formats and vocabularies. The common framework addresses issues associated with these facets by endorsing specific standards and protocols and listing recommended methods and practices. The ultimate intent of these endorsements is to aid in the creation of value-added products such as data portals, visualizations, and other tools. The recommendations presented in this paper are limited to Earth observation data and are made within the context of the Common Framework for Earth-Observation Data. The common framework adopts the definition of Earth observation data used in the 2013 National Strategy for Civil Earth Observations (Executive Office of the President, 2013): '[We] use the terms "data" and "Earth observations" interchangeably to mean geo -referenced digital information about Earth, including the observations, metadata, imagery, derived products, dataprocessing algorithms (including computer source code and its documentation), and forecasts and analyses produced by computer models. Non-digital data, published papers, preserved geological or biological samples, or other media that have not been digitized are not included in this definition. . .' This paper is a result of the recommendations distilled from use cases provided by three cloud vendors (Amazon, Google, and Microsoft) and used to assess NASA's existing data system. The provided use cases described how Earth observation data would be used by cloud vendors and also documented the vendors' experiences when interacting with data systems at different Federal agencies and organizations. Because the lessons learned from these use cases may be applicable to data management at other agencies and organizations, the resulting recommendations have been synthesized in this document. This paper thus intends to provide an integrated set of guidelines for evaluating and improving existing data systems in the context of high-volume data transfers. This paper further recommends that others follow the same guidelines to facilitate efficient access and improve data usability.

Data Search and Discovery Services

These services enable search and discovery of relevant datasets from different distributed data archives. The recommendations listed below focus on automating this process to enable bulk downloads and to preserve synchronization of data holdings.

Search and Discovery

• Provide a single, authoritative catalog for federated data systems that contains all data holdings.

• Ensure the catalog contains a complete and accurate representation of the data holdings at any time and is consistently updated. • Provide a complete dataset metadata listing, or catalog file, for download in a simple machine-readable format such as JSON (2017). The catalog file should:

• List all available data products.

• List all data granules for each data product with data access URLs.

• Utilize an efficient hierarchy where needed to minimize paging.

Rationale:

In order for users to efficiently search for and discover data, the authoritative metadata catalog must be accurate and up-to-date. Data that cannot be discovered through search via the catalog do not exist. In addition, cloud vendors utilize large automated systems to query catalogs to obtain all the metadata information needed to bulk download data, and they require a scalable method to fetch the entire/complete metadata catalog that is also easy to traverse. This could be the API so long as it can handle the large traffic loads. A machine-parsable catalog file that lists all dataset metadata is a simple, scalable, and robust mechanism that can address this need. This catalog file should include high-level information for each data product such as the product name, dataset description, reference documentation links, and any other relevant information users need when selecting a product to use. A complete listing of the data granules for each data product with access URLs is required in order to download the product. Finally, utilizing a hierarchy ensures that the catalog file does not grow unwieldy and makes parsing efficient.

Data Notification Services

• Develop a lightweight push notification feed to notify users of new datasets and granules and version updates. The notification system should:

• Be based on an HTTP post request to a URL that is registered to a user.

• Distribute a notification message that is machine parsable. • Allow users to subscribe to a notification feed for individual datasets.

Rationale:

A push mechanism places control of the curated archives directly in the hands of the data center and eliminates polling latency (i.e., the latency introduced by the rate at which users are able to monitor catalog files to detect new or updated data). A push mechanism also has the significant advantage of low latency for near-real-time data. An effective notification message provides enough detail on a dataset update to allow the user to immediately download and ingest the new or updated data if desired.

Data Access Services

While data access services provide users with various methods of retrieving data with a range of functionality such as subsetting, these specific recommendations focus on access from different types of data servers to support bulk downloads.

Recommendations:

• Provide data access using HTTP/HTTPS or FTP file downloads without restrictions or with basic authentication headers. Avoid stateful authentication mechanisms that require the user to enter through a login form each time. • Allow parallel downloads. If there must be a limit on parallel downloads, ensure that the limit is high enough to completely download large archives in a reasonable amount of time. Avoid requirements that all connections in a session come from the same IP address. Designate a technical point of contact to address questions concerning download limits (see Section 5.1).

Rationale:

A system acquiring data may not be a simple computer or virtual machine (VM) running conventional scripts. For example, cloud vendors have a whole distributed system for managing the retrieval of data from partners at scale. This system does not interact very well with stateful sessions, which generally operate under the assumption that there is a single machine at the other end of the line.

Data Documentation Services

Data documentation services are needed to ensure that the data are used correctly. As such, these recommendations include ensuring that data transferred remain in sync, there is no data corruption during the download process, and the data are read correctly by the analysis/visualization software.

Metadata

Data Version Information

• Provide metadata fields that flag when a dataset is complete and also flag when the dataset has changed. • Ensure the version number in metadata fields is modified whenever the data have been updated.

Rationale:

It is important for data users to know when a particular dataset is complete and when it has changed. Proper versioning not only ensures that users do not unknowingly use stale data but also supplies users with the ability to quickly determine whether or not they have the most current version of the data.

Data Integrity

Recommendations:

• Ensure metadata records include fields for both the file size and a checksum (preferably MD5) for each granule file.

• Checksums can be used to track updates to granule files. • Provide a complete listing of files for datasets that include a variable number of tiles so that a user can determine which tiles are legitimately missing.

Rationale:

The data catalog should include enough information to allow the user to verify whether they have obtained an accurate and complete copy of the data. The file size, in conjunction with a strong checksum, can serve as an initial verification during the download stage. Strong checksums prevent unnecessary downloading and reprocessing of unchanged files after a version update. In addition, a list of legitimately missing tiles clarifies for a user whether all available data has been downloaded and whether data should ever be provided for a given tile.

Data

Data Formats

• Utilize standard file formats and minimize the use of esoteric file formats.

Rationale:

Data provided in a standard file format do not require special readers and as such can be quickly and easily used. These standard formats also allow data to be imported into major GIS packages without additional effort.

Data Projections

• Utilize standard (common) map projections and coordinate systems where possible.

• Provide and support software tools to handle specialized projections and coordinate systems (GDAL, 2017;Proj4 2017, etc.).

Rationale:

The utilization of common coordinate systems and map projections minimizes the possibility of misuse of data and failure of tools during data use.

Other Support Services

These recommendations cover customer (user) support services needed specifically for customers utilizing large volumes of Earth observation data.

Technical Support

• Provide a clear point of contact for technical support and other questions related to data access mechanisms and networking issues. Technical support must be able to communicate directly with cloud vendor network engineers to support robust high-bandwidth connections. Ensure TCP/IP configurations on servers are optimized to maximize transfer rates. • Establish a communication channel such as a mailing list to provide updates on upcoming datasets, information about outages, and other relevant news related to data feeds.

Rationale:

A clear point of contact enables cloud vendors to distribute data with high reliability and ensures a timely response. A rapid response time is important due to the large number of end users that may be indirectly affected.

Conclusion

The recommendations presented in this paper are distilled from use cases provided by three cloud vendors (Amazon, Google, and Microsoft) and are based on their interactions with data systems at different Federal agencies and organizations. These specific recommendations range from obvious steps for improving data usability (such as ensuring the use of standard data formats and commonly supported projections), to non-obvious undertakings important for enabling bulk data downloads at scale. These recommendations identify the need for a single, authoritative catalog that contains all the metadata records for the data holdings of a federated data system, as well as the need for improved data management processes to ensure this catalog is consistently updated and the metadata records accurately represent the data holdings at any given time. While improving the overall existing metadata quality is always important for facilitating data search, access, and usability, these recommendations identify specific fields (e.g., data version and checksum) in the metadata record that are often overlooked. It is important for data centers to ensure that these fields have valid entries that are both correct and consistent. The need for new services such as automated data notifications, as well as new types of user support, are part of these recommendations. These recommendations have been used as guidelines in evaluating NASA EOSDIS (2017), and in identifying gaps and areas of improvement to support transfers of large volumes of data. These guidelines are applicable to data centers at other agencies and organizations and can be used for evaluating and improving existing data systems in the context of high-volume data transfers, thereby improving overall interoperability and data usability.
 Competing InterestsThe authors have no competing interests to declare.
Executive Office of the President 2013 National Strategy for Civil Earth Observations, National Science and Technology Council. Geospatial Data Abstraction Library. Available. Executive Office of the President 2013 National Strategy for Civil Earth Observations, National Science and Technology Council. Available at: https://obamawhitehouse.archives.gov/sites/default/files/ microsites/ostp/nstc_2013_earthobsstrategy.pdf. GDAL 2017 Geospatial Data Abstraction Library. Available at: http://www.gdal.org/.

Available at: https://earthdata. nasa.gov/about. National Science and Technology Council Committee on Environment, Natural Resources, and Sustainability and U.S. Group on Earth Observations Subcommittee Data Management Working 2016 Common Framework for Earth-Observation Data, National Science and Technology Council. Nasa Eosdis, Earth Observing System Data and Information SystemNASA EOSDIS 2017 Earth Observing System Data and Information System. Available at: https://earthdata. nasa.gov/about. National Science and Technology Council Committee on Environment, Natural Resources, and Sustainability and U.S. Group on Earth Observations Subcommittee Data Management Working 2016 Common Framework for Earth-Observation Data, National Science and Technology Council. Available at: https://obamawhitehouse.archives.gov/sites/default/files/microsites/ostp/common_ framework_for_earth_observation_data.pdf.

Introducing JSON -Java Script Object Notation. Json, Org, Json.org 2017 Introducing JSON -Java Script Object Notation. Available at: http://www.json.org/.


Clinical/Scientific Notes

BMDuncan Street
PhDChristopher A Halfpenny
PhDIan Galea
Clinical/Scientific Notes
Supplemental data at Neurology.org CNS INFLAMMATION OTHER THAN MULTIPLE SCLEROSIS: HOW LIKELY IS DIAGNOSIS?
The incidence, diagnostic landscape, and workload impact of CNS inflammatory diseases other than multiple sclerosis (MS) (CIDOMS) in a tertiary setting is unknown. We describe a retrospective case series of 64 patients identified over a 2-year period (2009)(2010) at the Wessex Neurological Centre in the United Kingdom, accounting for 4% of all patients seen at the center. As expected, neurosarcoidosis and neuromyelitis optica (NMO) were the most common diagnoses reached (14% each); other diagnoses singly accounted for ,10%. However, the likeliest diagnostic outcome (strikingly, in 25%) was nondiagnosis, despite intensive investigation and a mean follow-up period of 3 years. Undiagnosed patients with CIDOMS represented the largest workload of the neurology center.The Wessex Neurological Centre is a typical regional neurologic service with a catchment population of ;3 million in southern England and on-site expertise in neurology, neurosurgery, neuropathology, neurophysiology, neuroradiology, neuropsychology, neurorehabilitation, and neurophysiotherapy, across which specialist interest in neuroinflammatory disease is adequately represented. The study was approved by the University of Southampton's Ethics and Research Governance. A diagnosis of CIDOMS was made when there was unequivocal evidence of CNS inflammation (with certainty of an inflammatory etiology based on clinical, radiologic, CSF, and other laboratory findings) in the absence of MS or clinically isolated syndrome (CIS). Published diagnostic criteria (or, in their absence, published consensus opinions) were utilized to establish specific CIDOMS diagnoses (tables e-1 and e-2 on the Neurology ® Web site at Neurology.org). MS and CIS were diagnosed according to established criteria. 1,2 Detailed evaluation was conducted regarding resource utilization, including inpatient episode duration, imaging, invasive procedures, neurophysiology, nonneurology specialist reviews, and laboratory tests. In order to provide a sense of proportion to figures, a similar analysis was performed in patients admitted during the same period whose final diagnosis was MS. Further method details are available online (e-Methods).From a total of 1,525 patients admitted to the tertiary neurology center, 81 had a working diagnosis of CIDOMS, which was maintained in 64 cases as a final diagnosis. This represents an incidence rate of 11 cases of CIDOMS per million person-years. Seventeen patients with an initial working diagnosis of CIDOMS received a diagnosis of MS by the end of the follow up-period.

The incidence, diagnostic landscape, and workload impact of CNS inflammatory diseases other than multiple sclerosis (MS) (CIDOMS) in a tertiary setting is unknown. We describe a retrospective case series of 64 patients identified over a 2-year period (2009)(2010) at the Wessex Neurological Centre in the United Kingdom, accounting for 4% of all patients seen at the center. As expected, neurosarcoidosis and neuromyelitis optica (NMO) were the most common diagnoses reached (14% each); other diagnoses singly accounted for ,10%. However, the likeliest diagnostic outcome (strikingly, in 25%) was nondiagnosis, despite intensive investigation and a mean follow-up period of 3 years. Undiagnosed patients with CIDOMS represented the largest workload of the neurology center.

The Wessex Neurological Centre is a typical regional neurologic service with a catchment population of ;3 million in southern England and on-site expertise in neurology, neurosurgery, neuropathology, neurophysiology, neuroradiology, neuropsychology, neurorehabilitation, and neurophysiotherapy, across which specialist interest in neuroinflammatory disease is adequately represented. The study was approved by the University of Southampton's Ethics and Research Governance. A diagnosis of CIDOMS was made when there was unequivocal evidence of CNS inflammation (with certainty of an inflammatory etiology based on clinical, radiologic, CSF, and other laboratory findings) in the absence of MS or clinically isolated syndrome (CIS). Published diagnostic criteria (or, in their absence, published consensus opinions) were utilized to establish specific CIDOMS diagnoses (tables e-1 and e-2 on the Neurology ® Web site at Neurology.org). MS and CIS were diagnosed according to established criteria. 1,2 Detailed evaluation was conducted regarding resource utilization, including inpatient episode duration, imaging, invasive procedures, neurophysiology, nonneurology specialist reviews, and laboratory tests. In order to provide a sense of proportion to figures, a similar analysis was performed in patients admitted during the same period whose final diagnosis was MS. Further method details are available online (e-Methods).

From a total of 1,525 patients admitted to the tertiary neurology center, 81 had a working diagnosis of CIDOMS, which was maintained in 64 cases as a final diagnosis. This represents an incidence rate of 11 cases of CIDOMS per million person-years. Seventeen patients with an initial working diagnosis of CIDOMS received a diagnosis of MS by the end of the follow up-period. A breakdown of individual CIDOMS diagnoses is given in table 1 (for more detail, see tables e-1 and e-2).

Despite their small number (n 5 64) in comparison with MS patients (n 5 167), patients with CIDOMS required disproportionately longer inpatient stays, more intensive care, and larger numbers of investigations (see table 1 and figure e-1, p , 0.001 across all categories). Naturally, this resulted in higher costs (£520,409.18 vs £259,941.51, i.e., twice as much, p , 0.0001, see table e-3 and figure e-2). Among patients with CIDOMS, those without a diagnosis represented the largest workload of the neurology center, since they collectively needed the longest inpatient stay and the greatest number of investigations (see table 1).

The definition of CIDOMS did not include CIS, and it may be argued that cases of CIS with low risk of conversion to MS (with normal MRI and CSF 1 ) may turn out to have CIDOMS. None of the patients with a diagnosis of CIS converted to a diagnosis of CIDOMS in this study, but this may need longer follow-up, as illustrated by a recent case series. 3 However, categorization of low-risk CIS with CIDOMS and high-risk CIS with MS maintains nondiagnosis as the most common outcome in patients with CIDOMS (16 out of 78, i.e., 21%), and maintains patients with CIDOMS as still more resource-intensive than patients with MS (data not shown).

Two undiagnosed patients with CIDOMS had a clinical phenotype that resembled NMO spectrum disorder, though not typical (last 2 cases in table e-2). Restriction of anti-aquaporin antibodies to the CSF, 4 anti-aquaporin-4 antibody assay sensitivity, 5,6 and antimyelin oligodendrocyte glycoprotein antibodies 7 may be explanations. Yet again, a sensitivity analysis excluding these patients did not change conclusions.

Collectively CIDOMS are common and consist of up to 25% of the neurologic practice pertaining to inflammatory CNS disorders. The data highlight the importance of education regarding the diagnosis and treatment of these disorders. The striking finding that one-quarter of CIDOMS remained undiagnosed means that, in the absence of a diagnosis of neurosarcoidosis or NMO, an unclassified inflammatory disease is eventually more likely than other rarer diagnoses, which singly accounted for fewer than 10%. Broader serologic testing for individually rare antibodies and discovery of novel biomarkers should facilitate more rapid diagnoses in unclassified cases. Meanwhile, in the absence of a diagnosis, consensus guidelines to help recognition of antibody vs T-cell-mediated neuroinflammatory disorders will enable a rational empirical approach to treatment based on the likely underlying pathophysiologic mechanism.   Complete the AAN 2014 Neurology Compensation and Productivity Survey by May 9

The AAN launched its second annual Neurology Compensation and Productivity Survey in March and needs practicing US members and their practices to contribute their data. It is critical that all US neurologists and practice managers participate in the survey to ensure the most accurate and authoritative data representing the US neurology landscape. Visit AAN.com/view/2014NeuroSurvey to review preparation documents, including an FAQ and Quick Start Guide. Complete the survey by May 9 and get free access to the online results and the Neurology Compensation and Productivity Report, available in early July 2014. The cost to access the data and report for nonparticipants is $600 for AAN members and $1200 for nonmembers.

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From
Clinical Neurosciences (D.S., I.G.), Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton; and Wessex Neurological Centre (C.A.H., I.G.), University Hospital Southampton NHS Foundation Trust, UK.Author contributions: Dr. Street: data acquisition, data analysis, drafting of the manuscript, and review of manuscript for important intellectual content. Dr. Halfpenny: review of the manuscript for important intellectual content. Dr. Galea: data acquisition, data analysis, drafting of the manuscript, review of the manuscript for important intellectual content, and study supervision.

Study funding: Supported by the Wellcome Trust/Academy of Medical Sciences (starter grant to I.G.) and the University of Southampton's Faculty of Medicine (D.S.). Disclosure: D. Street reports no disclosures relevant to the manuscript. C. Halfpenny has received expenses to attend meetings from Biogen-Idec, Merck-Serono, and Teva-UK. I. Galea has received expenses to attend meetings from Teva-UK, has received commercial research grant support from Merck-Serono and IQ products, and holds research grants from the MS Society, Association of British Neurologists, Wessex

Table 1
1Invasive procedures included catheter cerebral angiogram; lumbar puncture; biopsy of brain, nerve, skin, pinna, or bone marrow; gastroscopy; bronchoscopy; or flexisigmoidoscopy. a Highest numbers.Number, percentage, and biennial total resource use of patients with CIDOMS by their final diagnostic categories

Diagnostic category
Number %

Total days in
hospital

Days on
ICU

All
imaging MRIs

Invasive
procedures
Neurophysiology

Specialist
reviews

Laboratory
tests

Unclassified
16 a
25 a
295.5 a
0
7 5 a
30 a
31 a
13 a
10 a
994

Neurosarcoidosis
9
14
278
13.5
59
18
19
4
5
1,021 a

Neuromyelitis optica
9
14
117
0
18
6
4
2
1
420

Cerebral vasculitis
4
6
246.5
2
52
10
16
2
9
707

Anti-VGKC encephalitis
4
6
93.5
0
19
3
6
4
1
227

ADEM
3
5
75.5
9
15
5
4
1
0
327

Postinfective
3
5
32
0
9
3
3
3
0
150

Anti-NMDA receptor
encephalitis

2
3
216.5
39 a
18
3
6
4
2
584

Paraneoplasia in lymphoma
2
3
87.5
0
27
8
5
4
0
326

Opsoclonus-myoclonus
2
3
53
0
6
2
2
0
0
134

Neuro-Behçet
2
3
31.5
0
7
3
3
2
2
92

Atypical MS
2
3
13.5
0
4
3
3
2
1
95

CRION
1
2
10.5
0
3
2
3
2
1
81

Anti-Hu syndrome
1
2
17
0
4
0
0
0
2
38

Lymphocytic hypophysitis
1
2
7
0
2
0
3
0
0
6 1

Neuro-Sjögren
1
2
4
0
3
3
1
2
1
3 0

Stiff person syndrome
1
2
9
0
0
0
0
0
0
1 5

Radiologically isolated
syndrome

1
2
0 . 5
0
1
1
1
0
0
1 5

Total
64
100 1,588
63.5
322
100 110
45
35
5,317

MS (for comparison)
167
100
689.5
0
57
109 106
43
5
3,735

CIS: low and high risk (for
comparison)

25
100
122
0
25
11
21
12
1
496

Abbreviations: ADEM 5 acute disseminated encephalomyelitis; CIDOMS 5 CNS inflammatory diseases other than multiple sclerosis; CIS 5 clinically isolated
syndrome; CRION 5 chronic relapsing inflammatory optic neuritis; ICU 5 intensive care unit; MS 5 multiple sclerosis; VGKC 5 voltage-gated potassium channel.

Medical Research, Medical Research Council, and the Engineering,
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CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. A Mckeon, S J Pittock, V A Lennon, Neurology. 76McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO- IgG. Neurology 2011;76:1108-1110.

Seronegative NMO: a sensitive AQP4 antibody test clarifies clinical features and next challenges. K Fujihara, M I Leite, Neurology. 80Fujihara K, Leite MI. Seronegative NMO: a sensitive AQP4 antibody test clarifies clinical features and next challenges. Neurology 2013;80:2176-2177.

Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. R Marignier, R Bernard-Valnet, P Giraudon, Neurology. 80Marignier R, Bernard-Valnet R, Giraudon P, et al. Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. Neurology 2013;80:2194-2200.

Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. J Kitley, M Woodhall, P Waters, Neurology. 79Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012;79:1273-1277.