The RUDY study platform – a novel approach to patient driven research in rare musculoskeletal diseases
Javaid et al. Orphanet Journal of Rare Diseases
The RUDY study platform - a novel approach to patient driven research in rare musculoskeletal diseases
M. K. Javaid 0 1
L. Forestier-Zhang 0
L. Watts 0
A. Turner 0
C. Ponte 0
H. Teare 3
D. Gray 0
N. Gray 0
R. Popert 0
J. Hogg 0
J. Barrett 0
R. Pinedo-Villanueva 0
C. Cooper 0 2
R. Eastell 5
N. Bishop 4
R. Luqmani 0
P. Wordsworth 0
J. Kaye 3
0 Oxford NIHR Musculoskeletal Biomedcial Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford , Oxford , UK
1 The Botnar Research Centre, NIHR Oxford Musculoskeletal BRU, NDORMS, University of Oxford , Oxford OX3 7HE , UK
2 MRC Lifecourse Epidemiology Unit, University of Southampton , Southampton , UK
3 Nuffield Department of Population Health, University of Oxford , Oxford , UK
4 Academic Unit of Child Health, University of Sheffield , Sheffield , UK
5 Academic Unit of Bone Metabolism, Metabolic Bone Centre, Northern General Hospital , Sheffield , UK
Background: Research into rare diseases is becoming more common, with recognition of the significant diagnostic and therapeutic care gaps. Registries are considered a key research methodology to address rare diseases. This report describes the structure of the Rare UK Diseases Study (RUDY) platform that aims to improve research processes and address many of the challenges of carrying out rare musculoskeletal disease research. RUDY is an internet-based platform with online registration, initial verbal consent, online capture of patient reported outcome measures and events within a dynamic consent framework. The database structure, security and governance framework are described. Results: There have been 380 participants recruited into RUDY with completed questionnaire rates in excess of 50 %. There has been one withdrawal and two participants have amended their consent options. Conclusions: The strengths of RUDY include low burden for the clinical team, low research administration costs with high participant recruitment and ease of data collection and access. This platform has the potential to be used as the model for other rare diseases globally.
Rare diseases; Database management systems; Dynamic consent; Patient reported outcome measures
There are between five and eight thousand identified
rare diseases [1–3]. Despite innovations in clinical
management of more common diseases, up to a quarter of
patients diagnosed with a rare disease can have a
diagnostic delay of between 5–30 years and 95 % of rare
diseases are still without specific treatments. The key
concerns for patients and families are to have more
information in terms of natural history and their
longterm health . Designing clinical trials for rare diseases
requires a detailed understanding of the contemporary
natural history of the disease to inform the selection of
clinically important outcomes, inclusion/exclusion
criteria, appropriate surrogate biomarkers and sample size
calculations [5, 6]. Furthermore, transformative
therapies for rare diseases are often costly and there is a
growing need to establish the cost-effectiveness of
such therapies in a real world setting, often within
observational studies .
One of the main challenges to studying the
epidemiology of rare diseases is in the ability to recruit and
retain a representative sample of patients in longitudinal
cohorts . Patients are often located across wide
geographical areas and institutions. This requires
national, inter-institutional and potentially international
collaborations to identify and contact patients.
Individuals with rare diseases can also have significant mobility
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issues in addition to other health issues, which may limit
their involvement in research studies that require
frequent visits and/or travel over long distances. Finally,
recruitment of patients attending secondary or tertiary
care settings can result in only those with more severe
phenotypes being studied, effectively excluding those
with a milder phenotype. The value of each participant
with a rare disease is high given the small pool of
potential participants. This heightens the importance of
designing studies that minimise participant attrition by
maximising participant satisfaction and engagement.
To develop a novel web-based reporting study with a high
level of participant engagement that improves
understanding of aspects of rare diseases through research. The
rationale of using a web-based approach was to address
the issue of engaging patients over a wide geographical
area and include those not attending secondary/tertiary
care services. The aim of the high level of participant
engagement is to ensure the study remains closely aligned to
the needs of the participants to improve satisfaction,
engagement and reduce attrition. The primary rare diseases
of interest are osteogenesis imperfecta, fibrous dysplasia/
McCune Albright syndrome, hypophosphatasia,
melorheostosis, myeloma, pregnancy associated osteoporosis,
X-linked hypophosphatemia, eosinophilic granulomatosis
with polyangiitis, giant cell arteritis, granulomatosis with
polyangiitis, polyarteritis nodosa and Takayasu arteritis.
For patients who either do not recognize these definitions
or have other rare disorders of the musculoskeletal system
or blood vessels, they are able to enter their diagnosis in
the ‘other diagnosis’ text box.
The RUDY study is currently designed as a five year
prospective cohort study, funded by a partnership
between the NIHR Rare Diseases Translational Research
Collaboration and the Oxford NIHR Musculoskeletal
Biomedical Research Unit, University of Oxford.
RUDY is a UK based national network of doctors,
researchers, patient groups, patients and families
working collaboratively to improve understanding of rare
diseases and enable the development of new tests and
treatments (Fig. 1).
Early in the design phase, the key patient groups in each
disease area were identified and patient representatives
were invited to join a Skype call to discuss potential
design aims. The patient groups identified three key
concerns: a) the lack of a comprehensive record of their
care and treatment with substantial issues when
transferring from paediatric to adult care, between specialists
and between hospitals; b) the lack of reliable information
on the Internet; c) significant regional variations in care
despite similar disease severity. It was also clear that
there was a lack of contemporary quality of life and
other patient reported outcomes in many rare diseases,
coupled with a lack of validated disease specific tools.
From the clinical staff perspective, it was clear there was
a need to minimize clinician/research nurse burden in
terms of recruitment and entering data if there was
going to be high uptake to RUDY, this would also cut
down on costs for recruitment and data entry. This led
to the decision to base the study on-line and implement
a generic suite of patient reported assessment tools
Fig. 1 Schematic of interactions between patient groups, patients, participants, clinicians and academics within the RUDY Study
covering quality of life as well as other aspects such as
pain, fatigue, sleep, anxiety and depression with minimal
burden on clinicians.
Governance structures: The Study Management Group
(SMG) manages the day-to-day running of RUDY. The
SMG meets weekly to: report on the development of
RUDY, including new features; respond to comments
from the patient forum and participants and deliver the
immediate and short terms goal of RUDY. The SMG is
made up of the principal investigator, project director,
database developer, data manager and ethicist. We had
initially included patients in the SMG but the attendance
to the weekly meeting was low, reflecting a high burden,
and so the patient engagement is principally performed
through the patient forum. Transparency in RUDY was
considered important to support engagement with
stakeholders. Three governance bodies were created to enable
the smooth running of the project and to ensure that
the collection, management, use and access to patient’s
data was conducted in a transparent and accountable
manner. These bodies are: the Data Outcomes Committee
which deals with issues related to the database content,
the Data Access Committee which reviews and approves
submitted analysis plans and other data access requests
and the Policy committee generates the terms of
publication of findings using the RUDY study data. Each of
these committees has a Chairperson, representation
from the SMG and Patient Forum and is ultimately
responsible to the SMG. Finally, an external advisory
board has been developed to advise on the strategic
direction of RUDY.
Eligible participants include patients with a rare disease,
blood relatives and partners of patients with a rare
disease. Individuals aged 0–100 years are eligible and a rare
disease is defined by a prevalence rate of less than 1 in
2,000 . For those aged below 18 years the permission
of a parent or guardian is required as well as assent of
Registration is done by the patient or their carers online.
The involvement of clinical staff is minimal with the
opportunity for clinician help if needed (Fig. 1). The web
address (https://research.ndorms.ox.ac.uk/rudy) has been
circulated to the major patient groups for rare diseases
of the musculoskeletal system and blood vessels through
presentations to patient groups as well as through
Google, Facebook and Twitter. Recruitment has also come
via word of mouth, with clinicians or patients
recommending the site to others.
The patient information sheets, guide to registration,
consent forms and assent forms for adults and children
are available to download as PDFs in the library section
of the website. Interested parties are invited to register
online in a three-stage process that includes patient
identifier and contact details, diagnosis and finally a
calendar function for when they want to be contacted by
telephone. The diagnosis is selected from a pre-defined
list and should their diagnosis not be present, it can be
directly entered into the ‘other diagnosis’ box.
The registration form is sent to the research
administration team and an appointment time is confirmed with
the participants by email. This form has a high security
with 256-bit encryption. The patient is contacted by
telephone and a trained researcher follows a script to
explain the study, ask for any questions and to ask for the
patient’s consent. Participants who give their verbal
consent are sent, by email or post, a consent form to
complete and return to the RUDY Study group. The
diagnosis of each participant is verified through contact
with the patient’s current clinician either in secondary or
primary care. This is usually in the form of a copy of an
appropriate outpatient clinical letter that includes the
participants name, address and diagnosis. Consent is
dynamic, allowing patients to alter their consent options
online in terms of access to health records, use of
samples and data and contact for other studies and updates.
Participant engagement and dynamic consent
From the outset, the aim of RUDY was to have a high
level of participant engagement and this is delivered in
part through dynamic consent . Informed consent is a
fundamental ethical requirement in clinical research
involving human participants. In face-to-face, paper –
based consent models, discussion between the research
team and participant for consent is a process that occurs
at the beginning of a study. It is then assumed that the
participants retain this record and do not change their
consent options unless they decide to withdraw from the
study. The dynamic consent model is an on-going
twoway dialogue between participants and researchers.
Participants are able to view their consent options on
line at any time within their secure web-space.
Participants can decide to change parts of their consent (e.g.
use of surplus tissue for research). Should this happen
any data/sample that could be affected is not destroyed
but is no longer made available for research as described
in the participant information sheet. Data and samples
that have been already anonymized are not affected.
Other consent options include contacting participants
about clinical studies, collection of surplus tissue and
linkage to other research databases.
Integral to participant retention is that participants
value being a part of the study. As part of this two-way
process, researchers post lay summaries of abstracts and
papers on the profile page of every participant that has
contributed data and/or samples. Participants can
contribute to the on-going development of the study
through continuous two-way communication with the
The aim is to improve participant retention but also to
improve the efficiency of the study design,
implementation and subsequent development. For those participants
who wish to play a greater role in the RUDY study, they
can join the Patient Forum that functions in three ways:
a) through six weekly Skype calls in the evening that last
up to 60 min. These are loosely structured around
feedback on current use of RUDY, upcoming RUDY website
updates, queries from SMG, and prioritization of future
work; b) on-going access to a secure online RUDY test
site where new or updated website features are available
to be tested by the forum before they are implemented
in the main RUDY website; c) discussion of new
research areas. For example, following guidance from the
Patient Forum, the study was restructured into a main
web-based study with, currently, four sub-studies
including clinic visits for assessment of physical function,
blood and urine tests, bone density test and skin
biopsies. The Patient Forum has also requested: inclusion of
questions that measure fatigue, a module where patients
can enter information about how their rare disease has
affected education, employment and social activities, a
diary of their health care usage, presence on Facebook
and Twitter and the inclusion of family members and
partners. All of these changes have required a substantial
amendment to the original research ethics committee
approval, which has been given greater weight because
the Patient Forum has requested these changes.
The annual stakeholder meeting provides the
opportunity for interested parties to be kept up to date and
maintain their involvement in the project. This meeting
includes members of the Patient Forum, clinicians,
researchers and the SMG.
Once consent is gained, participants are granted full
access to a secure personalised homepage on the study
website (Fig. 2). To allow for future linkage to other
national databases, additional demographic information
including postal address and items needed for the Global
Unique Identifier  are collected in addition to listing
their current secondary and primary care clinicians.
Participants are then directed to their landing page that
has three broad sections: “To do”, “Profile” and
“Timeline”. On the “To do” page is a list of questionnaires to
be completed online that are colour-coded depending
on their completion, with blue indicating new
questionnaires, orange for questionnaires that have been started
but are incomplete, and green for those that have been
Validated patient reported outcome questionnaires
used include, for adults, the EQ5D-5 L , SF-36 ,
Nottingham Activities of Daily Living score activity ,
Pittsburgh Sleep Quality Index , McGill pain ,
PainDetect questionnaires , Hospital Anxiety and
Depression scale , Functional Assessment of Chronic
Illness Therapy- Fatigue (FACIT-i); for children: the
PedsQL, Childhood Health Assessment Questionnaire
 and the Wong-Baker Faces questionnaires . For
adults with vasculitis: the Rasch-built Overall Disability
Fig. 2 Homepage of the RUDYstudy.org
Scale (R-ODS) for inflammatory neuropathy  and
vasculitis specific Patient reported outcome .
Each questionnaire has been checked where
appropriate by the respective licensing authority to confirm
the web version is an acceptable representation of
the paper form.
To record significant clinical events, participants are
offered a timeline to add events interactively.
Participants record the time in calendar day, month and/or
year or a range of years. At present this is focused on
fractures and includes the level of trauma and the site of
bones broken. There is an optional facility to record
aspects of management, including hospital site, length of
hospital stay, number of operations, outpatient
attendance, medications, physical therapy, recovery, use of
mobility aids and complications such as infection, delayed
healing and need for repeat surgery. These results are
then presented on a timeline for participants to view as
a diary format. The aim of the diary format is two-fold:
firstly, to satisfy a need from participants to be able to
record their clinical events in a secure and easily
accessible format; and secondly, to inform understanding of
the natural history of rare diseases.
Clinical Research opportunities
In addition to recruiting participants to the study and
inviting them to complete questionnaires, within the
RUDY ethics there are embedded sub-studies for clinical
assessment, blood and urine testing, skin biopsies for
generation of cell lines as well as body composition
assessment using dual energy X-ray Absorptiometry. In
addition, the RUDY study cohort represents a registry of
phenotyped patients who are asked whether they are
happy to be recontacted for other research studies as, and
when, approved by the Rudy Data Access Committee.
This allows other research groups for studies and trials to
approach RUDY for contacting potentially eligible
RUDY programming and security
RUDY is built with Laravel PHP open source framework
and has a modular design by a team of professional
software and web-developers mapping to the Rare Disease
Registry check list . This includes clear project
management, team based development, well-structured
commented source code and development guide, version
control and issue tracking of software and
documentation. The database information security complies with
UK NHS information toolkit v12 and all identifiable data
is 256 bit encrypted. Participant-identifiable data is only
accessible to the participant and the specific
administrators who need access to identifiable data to arrange
appointments, respond to queries and update confirmation
of diagnosis from clinicians. RUDY also includes specific
code to support future software developments and
linkage of RUDY information with other research databases
and information such as external tables of hospitals or
Researchers can only access non-identifiable data and
this can be exported in a comma separated-values (CSV)
format. Every user login to the RUDY database is
recorded in addition to software updates with a record for
what data was added, updated or deleted, by whom and
at what date and time. Access to individual records is
Social media involvement
Many rare disease groups have private Facebook pages
and discussion websites for patients. Following advice
from the Patient Forum, it was evident that presence on
social media would be beneficial for RUDY. It was also
clear that the RUDY Facebook page should not overlap
with existing closed Facebook pages and instead aim to
a) increase the profile of RUDY externally, b) improve
recruitment c) provide another method to offer updates
on RUDY. We submitted and gained ethical approval to
create a separate Facebook page (RUDYstudy) and
twitter account (@Rudystudy) for the RUDY study. These
are linked to the RUDY study website as well as the
social media pages of our charity and patient group
partners such as the Brittle Bone Society and Fibrous
Dysplasia Support Society UK. Posts and tweets include
updates on the number of patients recruited, new online
study events and website features, grants awarded and
results of research. To date the Facebook page has had
207 likes and the Twitter account 46 Followers.
Initial approval for the study was gained from the South
Central Research Ethics committee after review (LREC
14/SC/0126) in April 2014. The RUDY platform was
launched in June 2014 and by March 2016, the study
had recruited 380 participants, comprising 336 adults
and 46 children with the diagnoses shown in Table 1.
Approximately 20 % of requests for clinical confirmation
using a clinic letter have been returned.
Table 2 shows the proportion of adult questionnaires
completed for all diseases at baseline and 6 months
follow-up. The completion rate of questionnaires was
higher at 6 months (70.1 %) than baseline (56.8 %). The
completion rate was over 60 % at baseline and 75 % at
6 months for 5/5 for the vasculitides; of the rare bone
diseases, 3/5 diseases had greater than 60 % completion
at baseline and 0/5 over 75 % at 6 months. We then
compared the completion of the two quality of life
measures at baseline and follow-up by diagnosis for the most
common rare diseases (Table 3). The completion rates at
baseline varied from 54–100 % by disease. Of the
Table 1 Recruitment of participants by diagnosis up to March 2016
Osteogenesis imperfecta Type III
Osteogenesis imperfecta Type IV
Osteogenesis imperfecta Type V/VI/VII
Osteogenesis imperfecta Type unknown
Eosinophilic granulomatosis with polyangiitis
Granulomatosis with polyangiitis
questionnaires, the EQ-5D5L tended to be slightly better
completed than the SF36 at baseline with no consistent
difference at 6 months.
To date, one participant has withdrawn and two
participants have changed their consent options both to
opt in to either family tree linkage or linking of their
data to other research studies.
Rare disease registries are considered to be a key
component of research improving outcomes for patients. There
is an increase in the profile of research in rare diseases
 supported by changes in health policy in a number
of countries . A large number of rare disease
registries are currently being used globally [25, 26] and this
has led to the development of common elements for
databases including those within the EPIRARE  and
GRDR  programmes. However, online interaction
registries are still in their infancy and there are a number
of challenges to be addressed before they become a
common research methodology.
There was little difference between completion rates
between questionnaires. The higher completion rate at
6 months vs. baseline suggests that once patients had
started to complete questionnaires at baseline, they were
motivated to continue completing them at their next
follow-up. When comparing the shorter EQ5D-5 L with
the longer SF36, completion rates were only
slightly higher for the EQ-5D at baseline with no
consistent difference at follow-up. Further work is needed to
determine the benefit of measuring both. Between the
diseases, there was variation in completion rates, with
highest proportions in patients with vasculitis compared
with rare bone diseases. Participants with vasculitis are
more likely to be recently diagnosed and unwell and this
may explain the higher reporting rate. More work is
required to explore reasons why participants did not
complete their assessments and assess whether clearer
guidance is required to improve completion rates. For
example, when these findings were discussed with our
Patient Forum, it became clear that participants without
pain, may not realise they still need to complete the pain
assessments or be motivated to do so.
The RUDY database brings together several unique
features distinct from many other registries such as
online registration, dynamic consent and participant entry
of data in addition to significant involvement in the
decisions made about the creation, design and management
of the platform. This partnership with patients and
patient groups has been aimed at ensuring the optimal
experience for people in taking part in RUDY. This
approach has the additional benefit of minimizing the time
clinical and researcher staff spend on recruitment and
data entry, improving recruitment and retention.
Feedback from patients has shown that they find the
dynamic record keeping and the ability to print off their
data for personal use particularly valuable, which
Table 2 Baseline and 6 months completion of patient reported outcomes questionnaires
Activities of Daily Living
Pittsburgh Sleep Quality Index
Hospital Anxiety and Depression Scale
Participants were scheduled for the 6 months questionnaires after completing at least one questionnaire at baseline
aThese two questionnaires were introduced after a substantial amendment and those participants who had already completed a baseline questionnaire had these
questionnaires scheduled with their next assessment at 6 months
Table 3 Completion of Adult questionnaires at baseline and 6 months by diagnosis
Eosinophilic granulomatosis with polyangiitis
Granulomatosis with polyangiitis
Number of completed per number of submitted questionnaires by disease group shown, with percentages in parenthesis
supports the findings from other internet-based
registries . We propose that if patients are aware of
exactly what they are contributing to, and are updated
with how it is progressing the evidence base for their
disease, they will see themselves as partners in the
project, and thus may feel more empowered
Current research platforms, such as RD-Connect,
focus on developing a combined repository by
crosslinking data across clinical phenotypic and genomic data
and making this available for researchers . The
RUDY platform informs the clinical phenotype with
patient entry of phenotyping data within a dynamic
consent framework. It is appropriate for patients with rare
diseases who live in geographically diverse areas because
it allows frequent interaction without the significant
burden of travelling time and costs. Compared with more
traditional study models that require face-to-face
interactions between participants and researchers, this model
enables greater numbers to be recruited and it could be
used for participants based in other countries. Such an
international platform would deliver common data
collection with translation as appropriate with the required
linkage to national ethical and other regulatory
approvals. Use of similar web based portals with dynamic
consent may be applicable to research in other rare
conditions and also be effective in more common diseases.
There are a number of challenges to carrying out an
Internet based study. We were concerned that a number
of potential participants would not have access to the
Internet (or would not wish to use the Internet for this
purpose) and that this would restrict recruitment to
those with Internet knowledge and access. Our
experience has been that most patients have managed to
access their online page. The protocol provides that if
Internet access is not possible then paper-based forms
can be posted to individuals. To date, no participant has
needed paper-based support, because family members
have been able to provide Internet access. We recognize
that this may be specific to countries with reasonable
Two of the major concerns of patients were about the
quality of information on the Internet and variable care
between hospitals. Addressing these issues is
challenging, especially for the undiagnosed or newly diagnosed
patient. Providing evidence and consensus for care
pathways, both nationally and internationally, is one
potential solution and is actively being addressed for fibrous
dysplasia/McCune Albright Syndrome. Applying a fixed
age threshold for using participant consent vs. parent/
guardian consent with participant assent is challenging.
A number of authors have challenged the acceptability
and quality of childhood assent in the absence of a check
of the child’s maturity. The age threshold of 18 years
was a pragmatic decision.
Another difference between paper-based systems and
online systems is establishing a mean of confirming the
identity of participants registering on-line as well as
confirming the diagnosis. This is currently being
performed using a confirmation of diagnosis from their
current clinician with only a minority returning the
information and accounts for the large number of
“Other” diagnoses. Requesting copies of the clinical
records from participants may be a solution. The
completion of the baseline questionnaire rate needs further
work to encourage higher completion rates. While we
recognize that RUDY has substantial participant
influence, the lack of a set of criteria and standards means
that this cannot be quantitatively measured and
reported. Further work is needed to identify the metrics
for patient-centric platforms to enable benchmarking
and standard setting. Finally, paediatric recruitment is
lower than for adults and future work is needed to
understand the reasons for this and to guide future
development of RUDY.
To meet the needs of patients, clinicians and researchers,
we describe an innovative patient-driven web-based
platform with explicit and dynamic consent of participants,
online data assessment and engagement that could be
used as a model to follow in the development of other rare
We are grateful to the patients and patient groups (The Brittle Bone Society,
Fibrous Dysplasia Support Society UK, X-LH network UK, CLIMB and FindaCure)
who continue to contribute to RUDY and benefit from its outputs.
MKJ initiated the project and drafted the application. LFZ and NB
contributed to the paediatric aspects of the project, LW, CC, RE and PW
contributed to the adult bone aspects. AT, RP, HT and JH contributed to the
ethical approval and study management. CP and RL contributed to the
vasculitis aspects. DG contributed data management for the study. JB and
NG programmed the code. HT and JK contributed the dynamic consent
aspects and RPV contributed the health economic aspects. All authors read,
commented and approved of the final manuscript.
Consent for publication
Ethics approval and consent to participate
Ethics approval was given by the South Central Research Ethics
committee, UK after review (LREC 14/SC/0126) and participants gave
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