dataesr/scientific-paragraphs-categorization huggingface dataset:
Pain interference, quality of life and psychological variables The Patient-Reported Outcomes Measurement Information System (PROMIS)  19  questionnaires are used to assess various psychological and psychosocial variables. They include depression, anxiety, sleep disturbance, fatigue and pain interference. Two bespoke questions adapted from the existing population data ask about traumatic life experiences. The EQ-5D-5L  21  measures quality of life with a visual analogue scale and five items evaluating the impact of pain on the ability of the participant to perform everyday tasks. Two questionnaires assessing personality and in particular neuroticism are included in the DOLORisk protocol. The Ten-Item Personality Inventory (TIPI)  22  evaluates extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience.
Threshold tracking Threshold tracking is an electrophysiological tool that assesses nerve excitability  35. Nerve excitability measures are determined by the biophysical properties of myelinated axons and the axon membrane potential. The information obtained about nerve properties is complementary to conventional nerve conduction studies  35. In DOLORisk several measures of axonal excitability, such as refractoriness, supernormality, strength-duration time constant and threshold electrotonus, are assessed. The excitability measures are recorded from the motor and sensory divisions of the median nerve in line with published recommendations  36. Training will be provided to clinicians performing threshold tracking measurements to ensure the reliability of the data and harmonisation of nerve excitability protocols in all centres.
The wind up ratio (WUR) is not performed unless the patient is having CPM in which case it will be helpful to have a measure of central sensitisation. WUR is performed on the forearm instead of the dorsum of the hand in order to minimise the influence of peripheral sensory loss on detection of central processes. Thermal sensory limen is performed in those patients with peripheral neuropathy but not in peripheral nerve injury (a situation where it is less informative). The assessment of mechanical pain sensitivity is shortened and two rounds of tests are performed instead of the five rounds included in the full DFNS protocol. All other tests are identical to the DFNS protocol and all study sites will be trained and certificated in the DFNS protocol to promote standardisation. QST data is entered into the data analysis system, Equista (version 1.
Population cohort Generation Scotland: the Scottish Family Health Study (GS: SFHS)  47  and Genetics of Diabetes Audit and Research Tayside (GoDARTS)  48  are population-based genetic epidemiology studies. DNA, socio-demographic and clinical data are available for 24,000 GS:SFHS participants and 20,000 (9,000 with diabetes) GoDARTS participants across Scotland. Participants will be contacted by post and invited to complete the DOLORisk core protocol. After 18 months, enrolled participants will be invited to complete the same questionnaire to assess development, progression or remission of any pain. For the population cohorts it is estimated that between 7% (GS:SFHS) and 25% (GoDARTS) of those with chronic pain will have neuropathic pain  49. Therefore, 1,500 participants with neuropathic pain and 3,000 controls are anticipated from GS:SFHS and 2,000 participants with neuropathic pain and 4,000 controls are anticipated from GoDARTS.
Data analysis Sample size calculation The sample size for the protocol is largely based on the primary outcome, which is the number of participants to explore the genetic risk factors of neuropathic pain. The main comparison will be between those study participants diagnosed with neuropathic pain and those are diagnosed with no pain or pain of nonneuropathic nature. We will also be exploring physiological and psychosocial risk factors and these outcomes will require smaller sample sizes. For example, based on the CaTS power calculator  50  , we will have 80% power in an additive model with p=10 -8 , prevalence of neuropathic pain in the general population of 8%, with a disease allele frequency of 0. 30 (GS:SFHS) or 0. 38 (GoDARTS), and therefore a genotype relative risk of 1. 34. Based on the CaTS GWAS power calculator  50  , with 1,500 cases and 3,000 controls (as in the GS:SFHS cohort), we will have 82.
7% power to identify SNP associations with a significance level of 5×10 -8 , assuming an additive model, a minor disease allele frequency of 0. 3, a genotypic relative risk of 1. 35, and a prevalence of the diabetic neuropathic pain in the general population of 10% 1. For the extended phenotyping of painful versus painless diabetic neuropathy (estimating 1000 subjects in each group) we will have 80% power to detect an allelic odds ratio of 1. 7 at genome wide significance level (p<5×10  -8  ). We will also be able to crossvalidate between these cohorts. We have identified a further cohort of diabetic neuropathy individuals in Sweden who will be available for replication genotyping. In collaboration with the SUMMIT consortium, we would also like to combine data across diverse diabetic complications in order to enhance the power to detect genetic determinants of the microvascular complications of diabetes.
Data management The University of Dundee's Health Informatics Centre (HIC) Services acts as a hub for data management. HIC Services develops bespoke software to support secure data collection, provides recruitment support for clinical studies and manages a data entry service. All services provided by HIC are delivered within a secure Safe Haven environment to ensure data are managed safely and in compliance with Data Protection legislation. All HIC processes are governed by approved Standard Operating Procedures. GoDARTS and GS:SFHS datasets are already hosted on secure HIC servers. Participants' identities will be shielded at all times from the research team, according to the secure SOPs. External datasets generated by DOLORisk will be sent to HIC in anonymised format. When ready, these updated datasets will be transferred to the analytics platform held on a separate server and network from the HIC data management function within a remote-access Safe Haven for research projects.
It has full analytical functionality including software (e. g. R and SAS) and is supported by powerful processing. Remote access to the Safe Haven analytics platform is available to approved project researchers, after they have signed appropriate agreements. No individual-level data can be removed from the Safe Haven, but summary outputs of analysis are released, after prompt screening by HIC to ensure that no potentially identifiable information is included to reduce the risk of accidental disclosure. Clinical phenotype data will be linked in anonymised format to genomic outputs.
Ethics and dissemination Ethic approvals were obtained at the national level. Details can be found in Table  6. Participants are included in the protocol only after having given their written informed consent. Their decision whether to take part, or withdrawal during the course of the study, in no way alters their normal medical care. The signed informed consent is obtained by the clinician in charge of the patient or the healthy volunteer. Where possible, datasets will be made publicly available once the study is completed. Gene variants associated with neuropathic pain risk will be entered into the existing PainNetworks database  51  that undergoes longstanding curation by the London Pain Consortium. Transcriptional profiling data will be entered into painnetworks. org and ArrayExpress. We will enrich this with anonymised normative data on sensory profiling and physiological variables.
Not applicable Competing Interests: With several of the co-authors, I have collaborated on research projects, mostly as a part of various task forces and committees of IASP and its neuropathic pain special interest group (NeuPSIG). I believe these collaborations have not biased my review of the submitted manuscript. Reviewer Expertise: Neuropathic pain clinical studies, QST, somatosensory phenotypic I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. The questionnaire data are collected during the visit either on a paper clinical report form, or on a digital one, depending on the participating centre. The data are then entered manually by the investigator in the DOLORisk database through a bespoke interface.
In order to limit input errors, the interface includes data checks and acceptable ranges, for instance for age, height and weight. Oxford have access to the whole dataset and perform checks on the quality and completeness of the entered data. Issues such as missing data are sent back to the respective centres so that they can be addressed. The section on data management has been amended to include this information. 5 : the exclusion criteria for thoracotomy and mastectomy cohorts are quite different in terms of components not related directly to the surgery (e. g. cognitive disorders, substance use). Is there a rationale for these differences?.
the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Neuropathic pain assessment, QST, phenotyping, clinical trials I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Author Response 28 Jan 2019.
on behalf of  Oxford Innovation for Abide, Biogen ,  GSK ,  Lilly ,  Mitsubishi Tanabe ,  Mundipharma  and TEVA over the last 3 years. NA received speaker honoraria from  Pfizer  and reported fees for consultant services from  Novartis ,  Teva, Grünenthal, Mundipharma ,  Sanofi Pasteur ,  Aptinyx. ASCR has received funding from  Orion Pharma. ASCR undertakes consultancy and advisory board work for Imperial College Consultants-in the past 12 months, this has included remunerated work for:  Merck ,  Galapagos, Toray, Quartet, Lateral, Novartis and Orion. This work was supported by the  European Union 's  Horizon 2020 research and innovation programme  under grant agreement No  633491  (DOLORisk), and the  International Diabetic Neuropathy Consortium (IDNC)  research programme, which is supported by a  Novo Nordisk Foundation Challenge programme  grant (Grant number  NNF14SA0006 ).
hra. nhs. uk/planning- Committee on Medical 05/S1401/89 and-improving-research/ application-summaries/research- Dundee Pro Mixed 5500 Research Ethics summaries/dolorisk-dundee/ Smith, et al. 47 Yorkshire & The 15/YH/0285 Humber -South Yorkshire REC April 2018 Tayside 053/04 Committee on Medical Dundee Pro Diabetes 3000 Research Ethics https://clinicaltrials. gov/ct2/show/ NCT02783469 Hebert, et al. 48 Yorkshire & The 15/YH/0285 Humber -South Yorkshire REC.
Results: The French National Registry of FSHD patients was designed as a mixed model registry involving both patients and physicians, through self-report and clinical evaluation questionnaires respectively, to collect molecular and clinical data. Because of the limited number of patients, data quality is a major goal of the registry and various automatic data control features have been implemented in the bioinformatics system. In parallel, data are manually validated by molecular and clinical curators. Since its creation in 2013, data from 638 FSHD patients have been collected, representing about 21% of the French FSHD population. The mixed model strategy allowed to collect 59. 1% of data from both patients and clinicians; 26 and 14. 9% from respectively patients and clinicians only. With the identification of the FSHD1 and FSHD2 forms, specific questionnaires have been designed.
Though FSHD2 patients are progressively included, FSHD1 patients still account for the majority (94. 9%). The registry is compatible with the FAIR principles as data are Findable, Accessible and Interoperable. We thus used molecular standards and standardized clinical terms used by the FILNEMUS French network of reference centers for the diagnosis and follow-up of patients suffering from a rare neuromuscular disease. The implemented clinical terms mostly map to dictionaries and terminology systems such as SNOMED-CT (75% of terms), CTV3 (61. 7%) and NCIt (53. 3%). Because of the sensitive nature of data, they are not directly reusable and can only be accessed as aggregated data after evaluation and approval by the registry oversight committee.
Today various national registries have been or are being set up as reported in the TREAT-NMD website (http://www. treat-nmd. eu). They are either disease-centric in the United-Kingdom  [22] , Italy  [23] , Czech Republic, Netherlands, or part of larger registries including multiple neuromuscular diseases in the United States  [24] , Canada  [25] , Egypt, New-Zealand, Spain and Russia. A recent ENMC international workshop was dedicated to FSHD registries to ultimately harmonize data content to allow data sharing and match-making between registries  [26]. Here we report the creation of the French national FSHD registry and highlight its original design allowing a strong involvement of both patients and physicians, and its evolution since 2013.
Database structure The FSHD French National Registry is accessible at www. fshd. fr. It is composed of a secured-access database for registered users, and a freely accessible website for the general public. The database was built as a relational database (45 tables, 44 inter-table links and 533 fields) with the 4th dimension package (4D company, http:// www. 4d. com/). The website contains a mix of static and dynamic pages created upon request, using JavaScript and Ajax functions (https://www. w3schools. com/). The web interface was developed using the HTML5 and CSS3 standards with the Bootstrap 3. 1 package, thus allowing easy access to the website from multiple platforms (computers, tablets or smartphones). The database structure is modular allowing the addition of any field or feature. It contains both clinical and molecular data from FSHD patients collected via either self-report questionnaires, or clinical evaluation questionnaires filled by physicians, or both: The self-report questionnaire collects general data, a clinical self-assessment, genetic diagnosis results, and the patient's disease history (Additional file 1: Figure  S1 ).
The clinical evaluation questionnaire collects general data, diagnosis results, the patient's medical history, and a full clinical evaluation including a manual muscular testing (Additional file 2: Figure  S2  and Additional file 3: Figure  S3 ). The database is accessible to three different categories of users: 1) the patients who can fill self-report questionnaires and visualize both self-report and clinical evaluation questionnaires; 2) the physicians who can access their patients' data and 3) the clinical and molecular curators who ensure the high quality of data stored in the database through a manual quality control. For each patient, multiple self-report and clinical evaluation questionnaires can be created, generally every eighteen months. Self-report questionnaires can only be filled by patients with FSHD1, while two versions of the clinical evaluation questionnaire are proposed, one for FSHD1 and one for FSHD2 patients.
Data security The legal approval for the French FSHD registry has been obtained from the CNIL (French National Committee for Informatics and Liberty) under authorization No. 912291 on June 25th, 2012. The CCTIRS (French advisory committee on information treatment for research in health) also gave a favorable opinion No. 12. 004bis. Furthermore, a written informed consent was obtained from every patient before entering any data into the registry. Web access to the registry is secured by a two-factor authentication process combining a login and a password. An additional layer of security was added through the use of a session-specific token. Supplemental security measures have also been implemented, including login throttling and inactivity timeout. Daily backup and a log file are used to avoid loss of data in case of system failure.
Data collection: A mixed model involving patients and physicians The French National Registry of patients with FSHD has been developed to collect clinical and molecular data obtained from two sources: a self-report questionnaire filled by the patient and a clinical evaluation questionnaire filled by both the patient and the physician providing follow-up care. The questionnaires are sent to the clinical curator who controls the data quality prior to their import into the database. Once the patient has been created, a unique Personal Identification Number (PIN) code is sent to the patient and to the physician if a clinical evaluation form was filled. As patients are followed within a highly structured national network of reference centers, physicians can be granted access to their patients' data only or to patients registered in their reference center.
When creating a patient, the curator is automatically notified if this patient already exists in the database even he is affiliated to a different reference center. As previously mentioned, inconsistent or missing data are highlighted on the interface. Nevertheless, because questionnaires contain multiple pages, they can be filled through a multi-step process. To simplify data collection, the percentage of completion is displayed during the filling process. Additionally, an automatic summary form of missing data can be generated at any stage of the data entry process. The clinical curator can send the summary form with additional notes to the physician to collect missing data.
Data analysis functionalities Various graphical displays and tables have been designed to facilitate data analysis. The first set is dedicated to database evolution (number of patients and questionnaires) and data quality (with an emphasis on missing data). The second set extracts gender-and age-related data. The third set displays the medical specialties of the physicians who include patients in the registry. The fourth set contains data related to the molecular diagnosis: number of patients per laboratory and diagnosis results. The last one provides a graphical display of the patients' population based on selected clinical criteria.
Description of the FSHD French National Registry cohort The FSHD French National Registry was approved in June 2012 and set up in 2013. Considering the FSHD prevalence (1/20,000) and the French population (65 millions), we can estimate that about 3000 FSHD patients are living in France. During the last 5 years, we collected clinical and molecular data from 638 FSHD patients over the country representing about 21% of the French FSHD population. Data from 26% of patients were collected only from self-report questionnaires; 14. 9% from a clinical evaluation questionnaire; while for the remaining 59. 1% of patients, data were collected from both questionnaires (Fig. 2 ). The FSHD1 form of the disease currently accounts for 94. 9% of all clinical evaluation questionnaires. Improving the collection of data from FSHD2 patients is of paramount importance to gain insight into the natural history of the disease.
Besides, some FSHD registries are part of larger projects aiming at collecting data from major neuromuscular pathologies  [24, 25]. In the French FSHD registry, most items in the clinical evaluation form are mirrored in the self-report questionnaire to assess data quality and identify, for each item, who is best suited to provide the answer (either the patient or the physician). The French registry includes a strong patient-centered component. Indeed, the self-administered questionnaire has been designed by patients from the "groupe FSH", a satellite association from the AFM. The questionnaire design was part of a study sponsored by the Nice University Hospital (10-AOI-07). The French FSHD registry includes various tools to visualize and analyze data. For instance, it is possible to display the number of concomitant affections among patients suffering or not from a given affection as illustrated in Fig.
5  for a respiratory affection. Data from the French FSHD registry will thus allow assessing the nature and prevalence of comorbidities. Because this registry contains sensitive data, it was approved by the appropriate French review boards (CNIL and CCTIRS) and is hosted within a secured environment. The registry is accessible through a website (http://www. fshd. fr) containing the secured database itself with a freely accessible part. It contains general information on the French National Registry, the disease, the diagnosis, the associated French network centers, the state of research, reference publications and clinical trials. Links to other national registries are provided. Video and various documents are available and can be downloaded and used to join the registry. Newsletters also ensure regular information to patients about the registry evolution and advertise about forthcoming regional meetings with experts.
To help achieve a high data quality level required for a fruitful exploitation of the registry, we developed computer assisted data input. Various data consistency and data pre-filling rules have thus been defined to assist the curator (Additional file 4: Table  S1 , Additional file 5: Table  S2 ). After 5 years, the registry now contains about 21% of French FSHD patients. The proportion of registered FSHD patients is expected to be further increased through the strong support provided by the French association dedicated to Muscular Dystrophies (AFM-Telethon) and the active participation of experts from the French national network for rare neuromuscular diseases (FILNEMUS), which is one of the 23 rare disease healthcare networks built through the second French national plan on rare diseases.
To ensure interoperability at the global level, we use genetics standards coupled to clinical description. We therefore mapped these terms to ontologies, dictionaries and terminology systems to evaluate if one of the tested systems can be used for match-making  [31]. We observed that no system can be used to fully describe patients clinical features: the match rates of SNOMED-CT, CTV3 and NCIt are respectively of 75, 61. 7 and 53. 3%. Other ontologies and dictionaries, including HPO, contain less than 50% of terms used in the database. This underlines that interoperability between databases and registries cannot be ensured by a single approach and that systems must be able to handle heterogeneous queries to ensure efficient interoperability. While the rare disease field is trying to develop the Human Phenotype Ontology (HPO) and the Orphanet Rare Disease Ontology (ORDO) to simplify interoperability, our experience demonstrates that HPO still needs improvements to allow direct mapping of used clinical descriptions.
Conclusions The French National Registry of FSHD patients is part of a national effort to develop national databases  [22] [23] [24] [25]. These initiatives should now interact with other initiatives to build a European and/or an international FSHD virtual registry. The French registry is applying the FAIR principles as data are Findable, Accessible, Interoperable and Reusable. While individual data are protected, collaborators can have access to aggregated data after their requests have been granted by the registry oversight committee. This data sharing policy will evolve in the future with the emergence of the European Reference Networks (ERN) and the European Joint Program (EJP) on rare diseases and the associated actions to promote data standardization and interoperability. FSHD patients will benefit of the development and improvement of the French National FSHD Registry.