Building treasures for rare disorders

1. ^ Department of Paediatrics, AMC, University of Amsterdam, The Netherlands
2. ^ Department of Paediatrics, AMC, University of Amsterdam, The Netherlands
3. ^ Pitt-Hopkins Parents Support Group, Leidschendam, The Netherlands
4. ^ Cornelia de Lange Syndrome Support Group, IJmuiden, The Netherlands
5. ^ Marshall-Smith Syndrome Foundation, The Hague, The Netherlands
6. ^ Department of Paediatrics and Translational Genetics, AMC, University of Amsterdam, The Netherlands,*

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1. Introduction

One of the authors recently visited his 93-year-old father and found him sitting in the garden skyping using his iPad with a son in Italy. Indeed, 97% of all Dutch households has access to the internet (Accessed 15.04.2014).
The internet use is expanding worldwide, from 670 million people in 2002 to 2.45 billion in 2011, so nowadays 39 of every 100 world citizens are using the internet (Assessed 15.04.2014); www.thuisarts.nl (Accessed
15.04.2014)]. Similarly, our individual world is expanding: we can now access and share information with more people than ever and with people we would have never encountered otherwise.
A group that should benefit significantly from the gains of internet are individuals with rare disorders [Ayme et al., 2008]. In Europe a disorder is considered rare if it affects less than 1 in 2000 individuals, in the USA if less than 1 in 1500 (Accessed 15.04.2014); Rare Diseases Act, 2002]. Patients and their families are in great demand for validated comprehensive information.

Reliable information means information on large groups of patients. For rare disorders numbers are by definition small but should still be as large as possible. This means all patients from a single country, and for ultra-rare disorders one needs to think
global [Hennekam, 2011].

(Patient) support groups are extremely helpful in contacting such groups of individuals with rare disorders. They are often organized internationally and can easily reach out to their members around the world. They have their own website, Facebook page, or Google group, and communicate with their members by e-mail.
They have a digital infrastructure in place, and the trust of their members. Patients and their families are also the most important source of information: no-where the number of bits of knowledge and experience on physical complaints, development, behaviour, or reactions on treatments is as large as with groups of patients with the disorder involved. The sum of this knowledge is what affected individuals like to know and constitutes a treasure of information.

Here we describe the gains of collaborations between support groups and their physicians-researchers to obtain and distribute such treasures of information.

2. Research agenda

Physicians/researchers and support groups can assess knowledge gaps together: both prefer research topics where needs and wishes of affected individuals are met. Cornelia de Lange syndrome (CdLs) is a rare disorder characterized by intellectual disability, behavioural problems and many major and minor malformations, and most of these characteristics were in need of further evaluation.
A digital surveywas posted in the CdLs website asking families to indicate which research topic would be most important to them.
The families prioritized self-injurious behaviour, so such research project was started. Participation of the CdLs families was extremely high and allowed a fast and very effective study flow [Huisman and Hennekam, (in preparation)].

Researchers may fear support groups will only ask for studies that can be implemented in practice immediately. Marshal-Smith syndrome (MSS) is an ultra-rare entity with fewer than 100 patients described in literature to date. Main clinical features are intellectual
disability, unusual behaviour, kyphoscoliosis and characteristic face [Shaw et al., 2010].
The MSS support group was asked during a support group meeting which topic of research
they found the most important. The families realized the progressive osteoporosis was the main health issue and should be studied in detail before it could be treated. So they asked for basic research, i.e. to build a mouse model to study the influences
on bone of the gene causing MSS. The model has been build and studies are at present in progress [Thakker and Hennekam, (in preparation)].

3. Wikipedias

A Wiki(pedia) is an interactive website with information which allows users to add, modify, or delete content in collaboration with each other [Hu et al., 2008]. In wikis for rare disorders the number of potential contributors is small.We have built such wiki for MSS.

The basis was data in existing scientific literature. Blocks of information were written in lay terms on demarcated topics like vision, teeth, or heart and put on the MSS site. We had knowledge of affected MSS individuals living in 10 countries using 8 languages and arranged translation of the information in each language. The support group offered families private access to the information on the site, and all families added information. The medical advisors of the support group updated the information from time to time and families reacted to remarks of one another. 

The self-regulating capacity of the wiki was remarkable. The end result was detailed, cross-sectional information in lay terms on an ultra-rare entity that outclasses information on many common disorders. The information was also used to write an overview for a peer reviewed medical journal [Shaw et al., 2010], and access to information empowers patients [Ayme et al., 2008].

4. Waihonapedia

A wiki provides cross-sectional information but longitudinal information would be even more valuable. Some families use Facebook for this: they maintain a profile, often with personal information and pictures, and keep this updated. The use of Facebook
by many support groups show how important this is in communicating with one another. The disadvantage is that information is usually unstructured and not usable for research, and there are significant privacy problems.
We build on a joint database with longitudinal information for Pitt-Hopkins syndrome (PTHS). PTHS is an entity characterized by intellectual disability, major and minor malformations and unusual respiration patterns. We have built an extremely comprehensive
general questionnaire which asks questions about family, early history, physical problems, and cognition. To this we added a series of validated behavioural questionnaires. All have been translated in 7 languages. 

The questionnaire was made announced on various PTHS support group sites, and a key was forwarded to the families allowing them to put in data. Data have been entered by 100
families within a few months.

This extensive series of questionnaires was a one-off. The families receive now automatically a yearly request to provide an update using a short questionnaire, on somatic findings and especially on behavioural aspects. The information gathered systematically over a long period of time will become an increasingly valuable treasure for everyone involved in care or research for this disorder. We are now using the same systematics for individuals with CdLs.

Wikipedia is derived from the words ‘encyclopaedia’ and the word ‘wiki’ which means ‘rapid’ in Hawaiian. In analogy we have called our longitudinal database ‘waihonapedia’ from the Hawaiian word ‘waihona’ meaning ‘treasure’. The waihonapedias will provide
unprecedented information for everyone studying the disorder and everyone who plans interventions and would like to compare results to the natural history.

5. Conditions

A wikipedia or waihonapedia requires a reliable diagnosis in participating affected individuals. Confirmation by biochemical, metabolic or molecular tests will be required if possible, and otherwise diagnoses should be assessed by medical advisors of support groups with outstanding experience in the disorder. Our way of assuring reliably diagnosed participants only has been instrumental in detecting the gene causative for MSS as it allowed fast testing of a large group of MSS individuals through the support
group (indeed all have been found to carry a mutation [Schanze et al., 2014]). Our search for mosaicism in CdLS depended heavily on a large group carefully clinically diagnosed patients without a mutation, and the finding of mosaicism in 76% of until then
molecularly unproven CdLs individuals is of considerable significance for patient care [Huisman et al., 2013].

Security and privacy are main challenges of all forms of eHealth. In (ultra)rare disorders, there is a specific additional privacy concern next to safe data transmission: data can be present in only a limited number of individuals and may allow recognition of individuals if combined to other data such as age and country.We use the help of skilled computer professionals to ensure privacy.

6. Conclusion

Everyone wants to be special, but nobody wants to have a rare disorder. Individuals with rare disorders, their families and caregivers are in great demand of reliable knowledge about their disorder, but information is scarce and difficult to understand.

Affected individuals are usually extremely motivated to overcome obstacles as they experience their disorder 24/7. They constitute the major source of information, and are well contactable through support groups. The use of existing infrastructure of support groups can act as stepping stone to intensive collaboration between all involved, in many aspects of research, and particularly in gathering extremely valuable longitudinal data.

Digital tools empower this to a great extent. There are key concerns to solve, and awareness to increase. Still, collaboration between support groups and researchers, facilitated by modern media, can lead to better healthcare and quality of life for all with rare disorders.