Academic Productivity from Rare Neuromuscular Disease Registries: A Systematic Review

Background: TREAT-NMD is a global neuromuscular (NM) organization, created to enhance infrastructure to facilitate novel therapeutics reaching patients. One main activity is aimed at supporting NM disease registries. These rare disease registries are useful to fill knowledge gaps for various stakeholders in the disease community using real world data. Although it is important to understand how patient data is being utilized in the TREAT-NMD network and other rare disease registries, there is no systematic process or consistent metric for documenting the academic output from these registries. Objectives: The objective of this study was to determine the academic output from NM registries associated with the TREAT-NMD network, and the types of research the data is facilitating. Results: A systematic search of EMBASE, Medline, Cochrane Central and SCOPUS was performed from inception to November 24, 2021. The search yielded a total of 650 results, with 231 full text studies assessed for eligibility and a total of 97 studies that met the inclusion criteria. Conclusions: The results suggest publications from TREAT-NMD are mainly descriptive or methodologic. Rare disease registries, like the TREAT-NMD network, would benefit from clear and consistent metrics to facilitate reporting of academic output.


Introduction
TREAT-NMD is a neuromuscular network established in 2007 that provides infrastructure to help the development and translation of novel therapies to patients and establish best practice guidelines for neuromuscular disease (NMD) patients worldwide. The network was started as a European Union Network of Excellence, but has since developed into a self-sustaining international organization, uniting patients, clinicians, researchers, and industry in efforts to accelerate therapies for NMD (treat-nmd.org). The organization has several pillars of work with one of the primary efforts to support rare NMD registries. Patient registries have become an important research infrastructure tool for NMD facilitating epidemiologic studies, natural history profiles, clinical trials, and post marketing surveillance. Not only do these patient registries allow eligible patients to be connected to clinical trials, they also allow research criteria: 1) The primary content of the study was related to a neuromuscular disease and 2) The study finding, or results were generated using data directly from a TREAT-NMD registry. The study must specifically mention that the data was obtained from a TREAT-NMD registry. All study types whether in abstract or published manuscript form were considered for inclusion.
Two authors (CC and RS) independently screened the titles and abstracts, and selected articles for full text review. Full text articles were then reviewed for eligibility, with arbitration by a third author (TMN) for any differences that could not be resolved by consensus. We identified and removed duplicates if the studies appeared in multiple databases and if the same study was presented at multiple academic forums/meetings.
Eligible studies were then sub-grouped into four different categories including: Profile or methodologic, clinical research/guidelines, epidemiologic and basic science. Eligible studies were characterized as either abstracts or published manuscripts.

Results
The search yielded a total of 650 results, with 231 full text studies assessed for eligibility and a total of 97 studies included in the final analysis ( Figure 1). The main reason for excluding studies was because they did not include or use TREAT-NMD data in their study.
One of the studies was a basic science publication (manuscript), 22 were clinical research/guidelines (seven abstracts and 15 manuscripts) publications, six were epidemiology publications (four abstracts and two manuscripts) and 68 were profile/methodologic publications (31 abstracts and 37 manuscripts). In total, 42 were in abstract form and 55 were published manuscripts (Online Supplement).
It is worthy to note that publications may have been missed if they did not mention TREAT-NMD or TGDOC in the searchable fields, such as the title, abstract, keywords, and acknowledgements.

Discussion
The goal of this systematic review was to assess the type of academic output from the TREAT-NMD Global Database Oversight Committee (TGDOC). The TGDOC is a large network of largely academic and patient organization registries, containing data on thousands of patients [1][2][3] . As part of fostering this network, it is important to showcase work from the constituent registries, as well as understanding the different type of academic output from this valuable real-world data. However, it became clear there was limited benchmarking in the literature to fully assess the typical levels of academic productivity from and questionnaires on care and disease progression to be efficiently conducted. This is especially important for rare neuromuscular conditions where small patient populations jeopardize clinical trial enrollment. Patient registries serve to mitigate this risk through proper trial planning and recruitment. TREAT-NMD has established an oversight group (TREAT-NMD Global Data-systems Oversight Committee, TGDOC) to support NMD registry development and implementation, sustain relationships, and encourage best practices for NMD registries across the globe. Currently there are over 40 national and international NMD registries focusing on over 10 unique NMDs from over 25 countries affiliated with TGDOC (please see: https://treat-nmd. org/patient-registries/list-of-registries-by-disease for information on each registry). The various NMDs registries include: Charcot marie tooth disease, congenital muscular dystrophies, congenital myasthenic syndromes, Duchenne/ Becker muscular dystrophy, Facioscapulohumeral muscular dystrophy, GNE myopathy, Limb girdle muscular dystrophies, MTM and CNM registries, Myotonic dystrophy, and spinal muscular atrophy.
One of the primary objectives of NMD and other rare disease registries are to use the real-world data to fill knowledge gaps for various stakeholders in the disease community. This includes facilitating research and studying the patient populations of interest, with the overall goal of improving patient outcomes. However, there remains sparse literature regarding how to best measure the academic output, such as peer reviewed publications or scientific meeting presentations, from registries and the factors that contribute to productivity. These registries contain vast amounts of patient data and ought to be a source of significant academic activity.
Presently in the TREAT-NMD registry network there is no systematic process of documenting the academic output from the registries, however this is important to understand how patient data is being used in the constituent registries. The purpose of this study is to determine the amount and type academic output from TREAT-NMD registries, and the types of research the data is facilitating.

Materials and Methods
This systematic review followed the PRISMA 2009 guidelines. A systematic search of EMBASE, Medline, Cochrane Central and SCOPUS was performed from inception to November 24, 2021. An additional search of SCOPUS was also performed on November 24, 2021 to identify any relevant studies that mentioned TREAT-NMD in the funding and acknowledgements section. The search strategies are listed in Supplementary Appendix.

Study selection and eligibility criteria
Studies were eligible for inclusion based on two rare disease patient registries. Although rare registries may have different purposes and goals which may not include producing publications, the reality is that there is a substantial amount of patient data in these repositories 4 . However, the results from this review appear to show that there is a relatively small amount of research addressing epidemiologic or clinical questions that comes directly from these patient repositories. Furthermore, the literature contains little methodological research examining how a registry governance, objectives, and structure link to academic productivity. Therefore, we hope this study contributes to the discussion regarding the need to have consistent metrics and an elevated level of responsibility to report academic productivity that can be anticipated from a rare disease registry.
From this study we can take that many registries do an initial publication highlighting their existence and describing the characteristics and implementation of the registry. This was seen in our sample with 70% of the published/presented academic work was a methodologic description of the registry. There are a smaller number of studies that use the data for addressing a particular scientific question. The clinical studies were largely survey type studies examining patient reported outcomes such as quality of life, burden of illness or adherence to standards of care. Aside from answering relevant scientific questions, publishing from a registry serves many useful purposes including: 1) increasing the awareness of the existence of registry; 2) demonstrating a responsiveness to the patients and NMD disease community; 3) publicizing how the registry is stewarding the data; 4) exposing the registries to constructive criticism on which to drive improvements; 5) contributing to interoperability and collaboration; 6) inviting inquiry for regulatory, medicine authorization and health technology assessment processes; and lastly, 7) strengthening the science around registry methodology 5,6 .
The primary limitation of our study was that many TREAT-NMD registry studies did not include their affiliation with TREAT-NMD/TGDOC in the searchable fields, such as the title, abstract, and keywords. Thus, the included studies are not an accurate representation of the true number of studies from our constituents. We are aware through internal communications of our member registries of many studies that have used TGDOC data but were not identified in this search for this reason. To overcome this limitation, we subsequently searched SCOPUS database which allowed us to search the funding and acknowledgements section. However, we did not find a significant number of new studies. Going forward, we have appealed to our network registry leaders at our recent annual meeting to include their affiliation with TREAT-NMD in their future publications. Additionally, it is also possible that only the larger NMD centers/registries managed to publish relevant studies from their registries due to larger number of patients included. Smaller registries may need to merge under a TREAT-NMD/TGDOC, in a centralized registry to have the data used in a beneficial way for publication.
TREAT-NMD is a large inclusive organization that aims to advance diagnosis, care and treatment, facilitating the development of novel and existing therapies for patients living with NMD. We believe registries are an integral part of that effort but recognize there are still substantial steps in registry science and utilization efforts that need to occur to inform how registries can be better used as tools to facilitate research. There seems to be a need to develop pathways to better communicate and share registry data with all stakeholders, but more importantly with the patient stakeholders that have offered their valuable data to be included in registries.
Based on this systematic review, we plan to perform an additional similar review to search all rare NMD registries. This will hopefully allow us to achieve the objective of identifying all TREAT-NMD affiliated studies, as well as understand the patterns of academic productivity from registries. With a bigger sample size, we can also begin to try to understand other factors contributing to academic productivity. Factors such as size, location, affiliation with an academic institution, and the prevalence of the disease may influence the publication patterns.

Competing Interest
TMN has no conflicts of interest to declare.
MD has no conflicts of interest to declare.
NB is an employee of TREAT-NMD.