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Covid-19

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COVID-19 AND MS RESEARCH

On Thursday 12 March 2020 we said "see you tomorrow" to the colleagues, but that "tomorrow" (yes, Friday the 13th (coincidence or not?)) we didn't go to the office anymore. SARS-COV-2 has captured the nation and it is still holding on. That’s why we’re still spending our days at home.  Fortunately, with the current technologies and communication tools, a lot of work can be done from home. For example, during the pandemic we started a COVID-19 and MS Global Data Sharing Initiative, which is explained below. 

Multiple Sclerosis and COVID-19


Multiple Sclerosis, abbreviated as MS, literally means "multiple scars". It is an autoimmune disease in which the central nervous system (the brain and the spinal cord) is attacked by the body's own cells of the immune system. This leads to scarring, also known as lesions. The clinical signs of MS are very diverse and heterogeneous depending on the anatomical location of the inflammatory lesions. MS is currently still an incurable disease, but therapies are available that suppress the immune system and thus reduce the frequency of attacks. These therapies are called "disease modifying therapies" (DMTs). Compared to people who do not have MS, people with MS are generally more susceptible to infections such as the flu. So, you can understand that people with MS are worried during a pandemic like the one we are experiencing today (caused by an infectious virus).

COVID-19 doesn't need much introduction these days. It's the disease caused by the SARS-COV-2 virus, a coronavirus, that is going around the world at the moment and causes us all to stay "in our pits" (fortunately, we are allowed to get out once in a while). Viruses are tiny little balls that contain genetic material and need humans or animals to spread. The new coronavirus takes its task as a spreader very seriously and has managed to explore the whole world in just a few months. The small culprit of this pandemic has prickly particles on the outside as clearly shown in the most widely used scientific illustration of the moment. Undoubtedly you all know this figure: the grey sphere with red spikes created (only the illustration, not the virus of course) at the Centers for Disease Control and Prevention (https://phil.cdc.gov/Details.aspx?pid=23311). Because of these spikes the virus looks a bit like a crown and that's why it belongs to the family of coronaviruses (Corona is Latin for crown).

Some people are more at risk than others to get COVID-19. Think of people over the age of 65, people suffering from heart disease, but also people with a weakened immune system are seen as risk groups. This includes patients with MS who may or may not receive therapies that suppress the immune system. The arrival of this new virus raises questions for everyone, but especially for people with MS and their physicians. "Are we at greater risk of getting COVID-19?", "Should I still start or continue my current DMT if I get infected with the virus?", "Will COVID-19 infection cause my MS to relapse?" are some examples of questions they have, but they don't know the answers to.

Guidelines for people with MS have been drawn up by MS neurologists and organisations and can be found here. These guidelines will be adapted as soon as new findings are made. These new findings are therefore very important to inform people with MS and their doctors about what to do or not to do during this pandemic. Information provided should not just be based on assumptions (fake news is already being spread enough), but should be based on validated analyses conducted on sufficient data collected during the pandemic. And that is the point to which we contribute with the "COVID-19&MS Global Data Sharing Initiative".

Mission


MS is a relatively rare disease with a prevalence of about 2.3 million people worldwide. As a result, individual countries cannot collect enough data on COVID-19 in people with MS to provide reliable insights. Some countries had already started to collect data on COVID-19 in people with MS (e.g. Italy and the United Kingdom). Given the long-term benefits of harmonising the data collection, the MS International Federation (MSIF) asked whether the MS Data Alliance (MSDA) would be willing to participate in a major project to collect data on MS and COVID-19 on a global scale. Liesbet Peeters, the chair of the MSDA, also a data scientist at the University of Hasselt (BIOMED and the DSI) and not afraid of a challenge, agreed. From then on (we are now mid-March 2020) the project had an extremely passionate project leader. No time to create TikTok videos, bake biscuits or queue at the local supermarket to hoard toilet paper at the Peeters house, because there was a lot of work to be done. The aim of the initiative is to inform the MS community during the pandemic, whereby the information is obtained by analysis on real-world data (data collected during the pandemic). In order to make this possible, MS and COVID-19 data that are collected all over the world are needed to reach a sufficiently large number of data. These data will initially be used to provide initial insights during the pandemic. In this way we want to be able to provide answers to the following questions:

  1. Are people with MS at greater risk for severe COVID-19 outcomes compared to the general population?
  2. Is the pattern of risk factors for COVID-19 outcomes similar compared to the general population? (e.g., age, comorbidities... ); Does the severity of MS have an effect on COVID-19 outcomes?
  3. Is there a difference in COVID-19 outcomes between untreated people with MS and people with MS on DMT drugs?
  4. Does the type of treatment have an effect on COVID-19 outcomes?

In addition to answers to these questions, we also want to share insights to stimulate and steer future research, because findings in the longer term will also be needed. In-depth analysis of datasets at population level, including medical history and follow-up information, will be needed to answer other research questions such as:

  1. Are people with MS more susceptible to COVID-19 compared to the general public?
  2. Are people with MS on a specific drug more susceptible to COVID-19 compared to the general public?
  3. What is the long-term effect of COVID-19 on the progression of the MS?
  4. What is the effect of treatment stop or switches on COVID-19 susceptibility and outcomes?

These questions are beyond the scope of our Global Data Sharing Initiative, but we aim share methodological insights gained during our short-term project. Hopefully this will allow us to encourage future research led by others within the MS community.

Generating answers in five steps, lots of goodwill and some coffee


How do you start such an initiative? How do we get the data? What data? Who collects the data and how do the data get to us? Who evaluates the data? Do we have enough coffee?!
The patient is waiting and it is our job to find answers to their questions regarding COVID-19 and MS as quickly as possible. We immediately brainstormed and took action at an unprecedented pace.
There are a huge number of people involved in this initiative to get to what we are aiming for. Everything starts with an extensive network to consult. Fortunately, the MSDA and MSIF have a large number of connections that they can contact, which they did as quickly as possible. There are already a number of initiatives around the world that collect MS data from patients digitally. It varies from initiative to initiative whether this data is collected by physicians, by MS patients themselves or by both. So, it was very important to get these initiatives on board. Mails were sent, phone calls were made and a first meeting was set up to get an idea of the willingness to participate in the Global Data Sharing Initiative. As no one had considered a COVID-19 outbreak this year when applying for scholarships in 2019, there is no funding available specifically to support this project. A serious dose of goodwill and motivation of people with the necessary technical knowledge and ability to participate are therefore essential. Fortunately, the participants of the meeting saw the usefulness and need of the project and there was enough enthusiasm to continue. It had to be decided as soon as possible which variables were important to collect: the so-called “COVID-19&MS core data set” had to be decided on. To this end, a task force was set up that, among other things, examined the literature, but also focused on the existing questionnaires of initiatives in Italy and the United Kingdom, among others. After this we could really get started. Approval was obtained from the ethics committee in no time and, together with a company in legal counselling, lawyers and data protection officers, we looked at how we could make everything happen as quickly as possible and, above all, legally.
The project can be divided into 5 phases, which are shown in the figure below and also described below.

 

1. Data collection

The collection of data can be done in two ways:

  • Via national registers and cohorts (left on the figure): these are the initiatives that in any case already collect MS data and have already been briefly mentioned above. These initiatives will use their own standard procedures during the Global Initiative. The Registries are therefore also responsible for local ethical and privacy issues involved. These registries collect data reported by MS patients themselves and/or by their treating physicians. They are asked to implement the COVID-19&MS core dataset to the possible extent. Of course, the registries remain the owner of their data.
  • Via direct input into a central platform, the "fast module" (right on the figure): We encourage everyone to share data via the existing registers, but if for some reason (e.g. because they don't have time to go via a register) patients or clinicians were not able to do so, it is also possible via the Fast Module. This in turn concerns data that is entered by people with MS as well as healthcare providers.

The reason why we prefer that the data collection is done by the registers, is because the data collection through the "Fast Module" does not offer long-term perspectives. These data are fully deidentified and can never be linked again to the patient in question. The Fast Module also contains only the questions of the COVID-19&MS core dataset while the questionnaires of the registers contain many more questions by default and the patient data often go back further in time (medical history).

2. Sharing the collected data

In order to get a large amount of data, it is necessary that the data collected in different countries is also shared and ends up in one central place. The registers will create an export, a "dump" of the COVID-19 dataset. This dump (deidentified data) will be imported into the central platform that was kindly provided by QMENTA. This can be done in different ways and the registries get support from the MSDA and QMENTA where necessary. Each data custodian will also have access to their data in the platform.
We advise the data custodians to create this subset of data using a transformation code that will allow updates of the dump on a regular basis (preferably once a week), because we do not work with a static database in this project. Indeed, every week (if possible) we ask the custodians to upload new data. So, the database grows every week.

3. Data cleaning and preprocessing

The data custodians together with a so-called "data wrangling team" will clean up the data (not that they are dirty, but believe me: data cleaning is necessary) and "pre-processes" so that the data has the right form in order that downstream analyses can be performed.

4. Data analysis and 5. Feedback of results

The data of all registers and also the data of the fast modules come together in one central platform. Data from each register will be labelled in such a way that they can be linked back, in case this should be necessary. All combined data (from the registers and the fast modules in the central platform) will be checked and analysed by an analysis task force consisting of epidemiologists/biostatisticians in order to come to initial insights. As soon as a certain threshold of reliability and accuracy is reached, the platform will be made interactive so that people with MS, clinicians and researchers also have access. They will also be able to view and query these data/results.

So, as soon as the accuracy and reliability of the data is high enough, the platform will become interactive and data custodians, patients, doctors and researchers will have access to the data. These data are deidentified (outside the of scope of the GDPR) and will remain in the platform until the analyses are completed (provisionally until 31 December 2020). After that, they will be removed from the platform and return to the custodians.  

One-month time: all the difference in the world


A lot can happen and change in a short time. From one day to the next, for example, you end up in a lockdown world and from one day to the next you get involved in a project of a size we've never stood for before. After one month we had made already a lot of progress. There are currently 8 registers/cohorts who have signed a Data Transfer Agreement and who (will) officially share data in the central platform. There are 15 other initiatives that also collect and plan to share data. In total (including the fast module) 1233 patients and 120 clinicians already shared data in the central platform on May the 6th.
Because it was not possible for a number of registries to sign the Data Transfer Agreement (due to local privacy issues) and they will therefore not be able and allowed to share patient data in the platform, we have devised an alternative in which they share insights instead of patient data. Our team of analysts and data wranglers have written R- and Python scripts that the registers can run on their collected data. Instead of the data itself, they will share insights in the form of "counts". This is what is called a federated system. The gathering of data at one single point is called a centralized system. In the federated system the data does not leave the register. Therefore, it is outside the scope of the GDPR.

Who does what? #DataSavesLives


To recap: in our project we collect as much patient data as possible on MS and COVID-19 during the pandemic in order to be able to analyse these data and come to reliable insights. These insights will help MS patients and their physicians to make decisions during the COVID-19 pandemic.

It may sound simple, but there is a lot involved. Such a project can only be successful if many people work together. Let's sum up who is involved.

MSIF is a global network of 48 MS organisations, people with MS, volunteers and staff from all over the world. MSIF aims to inspire, mobilise and bring the world together (but at least 1.5m away these days 😉) in order to improve the quality of life for all those affected by MS. The ultimate goal is to achieve a world without MS. Worldwide there are about 2.3 million people living with MS, but a large proportion of these people have little or no access to support, which, together with sharing accurate information, is vital for people with MS and their families. MSIF aims to increase awareness of the disease. They also support scientific research to improve MS treatments.

The MSDA is a new player in the field that has only just been launched in November 2019. It is an independent multi-stakeholder initiative that operates under the umbrella of the European Charcot Foundation (ECF) in which ECF acts as the legal entity. In turn, ECF is an independent non-profit organisation with the aim of advancing MS research.

The stakeholders of the MSDA are regulatory authorities, people with MS, patient organisations, data custodians, industry partners, physicians and researchers. As its name suggests, the MSDA focuses on data. We believe that the care of people with MS can be improved by using existing data (real-world data). Together with its partners, the MSDA tries to make people aware of the principle that the use of real-world data is of great importance in research. This real-world MS data should therefore also be accessible and collected in a reliable and transparent way.

The daily coordination of the COVID-19&MS project, management, communication and legal council is led and carried out by Liesbet Peeters (UHasselt and chair of the MSDA), Nick Rijke (MSIF), Lotte Geys (UHasselt, MSDA), Gunther Meyer (external lawyer), Jan Samyn (ECF, MSDA), Clare Walton (MSIF), Victoria Gilbert (MSIF) and Margo Heremans (ECF, MSDA).

QMENTA is the company that has developed and kindly provided the central platform where the data comes together and is analysed for the Global Data Sharing Initiative.
In pre-COVID-19 times they mainly focused on storage, processing and visualization of medical imaging (MRI) in the brain. They offer state-of-the-art medical imaging algorithms in a way that accelerates the development of new therapies for neurological diseases by using their platform. The Q in QMENTA stands for "quality", but also "quanty", which refers to the large amount of information that can be extracted from complex MRI images. "Menta" comes from the Latin mentis (the mind) and refers to the focus on the brain.

Landon McKenna, Nikola Lazovski and Paulo Rodrigues are responsible for the development of the central platform for the global initiative and work around the clock to keep everything on track.

The Data Wrangling Task Force ensures that the data collected by the registries/cohorts are properly imported into the central platform, and also ensures that the data in the platform is "cleaned up" and pre-processed in such a way that it can be used for analysis. This task force consists of Tina Parciak (University of Göttingen, MSDA), Luc De Raedt, Clément Gautrais, Yann Dauxais (KU Leuven) and Lars Forsberg (Karolinska Intitute in Sweden).

The Analyses Task Force consists of experts in epidemiology and biostatistics. They have drawn up a list of hypotheses, research questions and an analysis plan at the start of the project. During a short hackathon, they will review the first analyses together and decide when the platform will have sufficient high-quality data to proceed and make the platform interactive. This task force consists of Jan Hillert and Tim Spelman (Karolinska Institute), Tomas Kalincik and Steve Simpson-Yap (Melbourne University), Yves Moreau and Edward De Brouwer (KU Leuven), Ashkan Pirmani (KU Leuven and University Hasselt), and Gilles Edan (ECF).

The MS Registers/cohorts that currently (on 7 May 2020) have committed to actively participate in the project are listed in the table below.

Currently participating COVID-19 in MS data collection initiatives

Initiatief dat COVID-19 & MS verzamelt Data gerapporteerd door patiënten Data gerapporteerd door artsen

ABEM

Ja

Nee

AMSLS

Ja

Nee

Australia and New Zealand COVID-19 Data set

Nee

Ja

Bulgarian SmartMS COVID-19 dataset

Ja

Ja

Cleveland Clinic MS COVID-19 Registry

Ja

Ja

COViMS Registry, a North American COVID-19 and MS Reporting Database

Nee

Ja

EMA

Ja

Nee

French COVISEP

Nee

Ja

German MS Register, by the German MS-Society COVID-19 survey

Ja

Ja

HOLISM

Ja

Nee

Icompanion

Ja

Ja

iConquer MS COVID-19 Survey

Ja

Nee

International MuSC-19 Case Reporting platform linked to the Italian MS Register

Nee

Ja

LEOSS Registry

Nee

Ja

MSBase  COVID-19 Substudy

Nee

Ja

NeuroTransData

Ja

Ja

OptimiseMS

Nee

Ja

REDONE

Nee

Ja

RELACONEM

Nee

Ja

Swedish MS Registry COVID-19 module

Nee

Ja

The Danish Multiple Sclerosis Registry

Nee

Ja

The Spanish MS Registry

Nee

Ja

UK MS Register COVID-19 CRF

Ja

Ja

Currently, there are 11 registries/cohorts collecting (or preparing to collect) patient-reported data and 18 registries/cohorts collecting (or preparing to collect) clinician-reported data. Abbreviations: ABEM: Brazilian Multiple Sclerosis Association; AMSLS: Australian MS Longitudinal Study; COVID-19: Coronavirus Disease 2019; COViMS: COVID-19 infections in MS Database; COVISEP: part of French MS Registry collecting data on COVID-19; CRF: case report form; EMA: Esclerosis Multiple Argentina; HOLISM: Health Outcomes and Lifestyle in a Sample of People with Multiple Sclerosis; LEOSS: Lean European Open Survey on SARS-CoV-2 Infected Patients; MS: Multiple Sclerosis; MuSC: Multiple Sclerosis and COVID-19; NTD: Neurotransdata; REDONE: Brazilian Registry of multiple sclerosis and neuromyelitis optica spectrum disorders; RELACONEM: part of RelevarEM registry that will collect the data of COVID-19.

Keep up to date?


On the website of the MSDA and MSIF you can find a large amount of extra information about the COVID-19&MS Global Data Sharing Initiative. If you are interested, you can subscribe to the MSDA and/or MSIF newsletter.
This video summarizes the project visually and briefly. Feel free to share it.