Digit-all: Rare Diseases

Abstract

Rare diseases are increasingly recognized as a global public health priority and contribute to significant and disproportionately high health system impacts. Accordingly, they present clinical and public health challenges, as well as opportunities for digital health solutions across the lifespan, including improved diagnosis, treatment, navigation and care coordination, and integration and coordination for broader societal and patient wellbeing. People living with rare diseases, individually and cumulatively, are digital disruptors. In this manuscript the authors describe some of the unique dynamics of the rare disease domain as they currently, or have the potential to in the future, apply to digital health; highlight some recent international rare diseases digital health initiatives; and touch upon implications for those with more common disorders.

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Creative Commons Attribution-Non Commercial 4.0 September 2020 • EMJ
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Digit-all: Rare Diseases
INTRODUCTION
Rare diseases are increasingly recognised
as a global public health priority.1 Whilst rare
diseases have a low prevalence individually, it
is estimated that the combined prevalence is
between 6 and 8% of the population,2 equating to
>400 million people globally. Most rare diseases
have a genetic association, and are often severely
debilitating, impair physical and mental abilities,
and shorten life expectancy.3 Rare diseases also
contribute to significant and disproportionately
high health system impacts, such as cost burden.4
These characteristics present clinical and public
health challenges, as well as opportunities for digital
health solutions across the lifespan, including
Authors: *Gareth Baynam,1 -7 Lynsey Chediak,8 Gemma Bilkey,1,9
Dylan Gration,4 Samuel Agyei Wiafe3
1. Oce of Population Health Genomics, Public and Aboriginal Health Division, Perth,
Australia
2. Department of Health, Government of Western Australia, Perth, Australia
3. Rare Disease Ghana Initiative, Accra, Ghana
4. Western Australian Register of Developmental Anomalies, King Edward Memorial
Hospital, Perth, Australia
5. Telethon Kids Institute and Division of Paediatrics, Faculty of Health and Medical
Sciences, University of Western Australia, Perth, Australia
6. Spatial Sciences, School of Earth and Planetary Sciences, Curtin University, Perth,
Western Australia
7. Faculty of Medicine, Notre Dame University, Fremantle, Australia
8. World Economic Forum, Precision Medicine Initiative, San Francisco, USA
9. Patient Safety and Clinical Quality, Clinical Excellence Division, Department of
Health, Government of Western Australia, Perth, Australia
*Correspondence to gareth.baynam@uwa.edu.au
Disclosure: The authors have declared no conflicts of interest.
Received: 28.07.20
Accepted: 21.08.20
Keywords: Digital health, phenotyping, precision medicine, precision public health, rare diseases,
undiagnosed diseases.
Citation: EMJ. 2020;5[3]:11-16.
Abstract
Rare diseases are increasingly recognised as a global public health priority and contribute to
significant and disproportionately high health system impacts. Accordingly, they present clinical
and public health challenges, as well as opportunities for digital health solutions across the lifespan,
including improved diagnosis, treatment, navigation and care coordination, and integration and
coordination for broader societal and patient wellbeing. People living with rare diseases, individually
and cumulatively, are digital disruptors. In this manuscript the authors describe some of the unique
dynamics of the rare disease domain as they currently, or have the potential to in the future, apply
to digital health; highlight some recent international rare diseases digital health initiatives; and touch
upon implications for those with more common disorders.
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improved diagnosis, treatment, navigation
and care coordination, and integration and
coordination for broader societal and patient
wellbeing (e.g., linkage to education, disability,
and community sectors). In this article, the
authors describe some dynamics of the rare
disease domain as they currently, or have the
potential to in the future, apply to digital health;
highlight some recent digital health initiatives
in the international rare diseases domain; and
touch upon implications for those with more
common disorders.
SO, WHAT IS DIGITAL?
Some Useful Definitions
Digital is defined as recording or storing
information as a series of the numbers 1
and 0, to show that a signal is present or
absent; using or relating to digital signals and
computer technology.5
“Digital health harvests data, information, and
knowledge in real time from all societal activities,
not just interactions with the health system and/
or data traditionally regarded as ’health’ data;
uses sophisticated analytics to distil knowledge
from these data; intervenes in the widest possible
range of societal and economic activities and
technologies to encourage and generate better
health and better value for health investments.”6
Digital health systems are not just about health
and health system workflows, they are about
life and life-flows. Comprehensive digital health
systems extend beyond illness into other areas of
the patient’s life. That is, the flows extend across
the breadth of human experience to include a
person’s health, family, education, (dis)ability,
economic (dis)advantage, and the community
to which they belong. They require real-world
data, information, and knowledge in real time,
from all societal activities, to generate better
health value. They also require approaches that
are person-centric, decentralised, or distributed,
and empower healthcare providers to actively
participate and partner with each other and their
patients, not simply to control a fixed outcome.
WHY DIGITAL HEALTH AND RARE
DISEASES?
In addition to the very significant patient needs,
there are a number of other dynamics of the rare
diseases domain that make it fecund for digital
health advances and implementation.
Digital People
Notwithstanding the complexity, fundamental
humanity, and multidimensionality of living with
a rare disease, rare monogenetic (single gene)
diseases may be as close to a causally binary
chronic disorder that medicine oers. That is,
the presence of a single causative factor, for
instance a mutation in one’s DNA, can invariably
(complete penetrance) or often (incomplete
penetrance) lead to a manifest disorder. Put
another way, a disruption in a digital (DNA)
code can invariably or often result in the
presence (1) or absence (0) of a chronic and
severe condition. People living with rare diseases
can be thought of as living digital disruptors;
their diseases can have a binary model and
they can shift the fundamental expectations
and behaviours in a culture, market, industry,
technology, or process that is caused by, or
expressed through, digitalcapabilities, channels,
or assets.
Signal-to-Noise Ratio
Signal-to-noise ratio is a measure used inscience
and engineering that compares the level of a
desired signalto the level of background noise.
A signal is a meaningful input whereas noise is
a meaningless or unwanted input. The severity
of rare diseases provides a high signal that is
primed for a (digital) readout. The high signal-
to-noise ratios found in rare diseases are caused
by the magnitude of both individual features of
rare disorders and other unusual signatures of
the condition itself that can be readily detected.
These signals are also grounded in molecular
biological pathways to provide insights into
disease pathogenesis and its management.
When combined, these factors provide clarity
from the extremity of rare diseases. Similarly, the
magnitude, and sometimes the relative speed
of impact from an intervention, may be overt,
which allows timely and eective monitoring.
Accordingly, William Harvey (1578–1657), who
was the first to describe the systemic circulation

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of blood pumped to the brain and body by the
heart, noted: “Nature is nowhere accustomed
more openly to display her secret mysteries than
in cases where she shows traces of her workings
apart from the beaten path; nor is there any
better way to advance the proper practice of
medicine than to give our minds to the discovery
of the usual law of nature by the careful
investigation of cases of rarer forms of disease.
For it has been found in almost all things, that
what they contain of useful or of applicable
nature, is hardly perceived unless we are deprived
of them, or they become deranged in some way.”7
Multisystemic
Cumulatively, rare diseases aect all body
systems, and individually they are often present
with multisystem features. They traverse all
medical specialities and the life-course. They
are also exemplars for systems biology and
the implementation of multi-omic approaches
(i.e., combinations of genomics, epigenomics,
phenomics etc). Because their individual rarity
is combined with many layers of common
elements, they require and are uniquely suited
to cross-border, multi-health system care. Rare
diseases are medically multisystemic, require
systems biology, and health systems approaches
that adapt to the flows of life.
Runs on the Board
The dynamics of rare diseases have already
supported the implementation of digital health
approaches in genomic healthcare, medical
imaging and deep phenotyping, and international
data sharing and matchmaking.8
Healing Hands
Caring for people with rare diseases requires
combining traditional and physical approaches
with modern technology. Put another way, there
is a need to meld high-touch digital (the digits
of healing hands) and high-tech digital
(technology) approaches.
WHAT’S HAPPENING IN DIGITAL
HEALTH FOR RARE DISEASES?
Increasingly, and particularly over the last 2
years, there has been global engagement and
convergence in digital health for rare diseases.
Some notable examples are touched upon below.
Rare Diseases International and the
World Health Assembly
The 23rd May 2019 marked a historic day for
the rare diseases movement, with rare diseases
featuring on the agenda of the World Health
Assembly (WHA) for the first time.9 Rare
Diseases International (RDI) contributed towards
the formal and informal events that shone a
spotlight on the importance of including rare
diseases in universal health coverage in order
to leave no one behind. At these events it was
noted that rare diseases are at the forefront of
digital health and they exemplify the high added
value of regional and global approaches. They
also showed that new digital tools are already
being used to address the challenges experienced
by the >400 million people living with a rare
disease, enabling them to connect highly isolated
patients, enable access to and acceleration of
diagnosis, refer to specialised medical expertise,
gather and share expertise on highly complex
care, and advance clinical research.
A formal side event, part of the ocial WHA
agenda and sponsored by permanent missions
from the European Union, Romania, and Kuwait,
used rare disease case studies to highlight the
potential of digital health to achieve universal
health coverage. The event was co-sponsored by
an additional nine Member States, demonstrating
the high level of interest and support.
The Global Commission to End the
Diagnostic Odyssey for Children with a
Rare Disease
The Commission is a global approach to
accelerate time to diagnosis for children living
with rare diseases.9 It uses a multidisciplinary
group of international experts to develop a
road map to accelerate the time to diagnosis
for children living with rare diseases. They also
develop, deploy, harmonise, and interoperate
digital tools developed through pilots that
traverse, but are not limited to, harnessing the
combined power of engagement and awareness,
genomics, deep phenotyping, and artificial
intelligence, whilst equitably scaling their
implementation. One digital tool that is currently
being implemented in the Global Commission
data ecosystem is Cliniface.10 This 3-dimensionsal
facial visualisation and analysis software
enables collaboration between clinicians and
researchers to advance understanding of facial

EMJ • September 2020 EMJ
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characteristics and their relationship with rare
diseases and their treatment.
World Economic Forum Precision
Medicine Initiative
Precision medicine can be defined as an
emerging approach for disease treatment and
prevention that takes into account individual
variability in genes, environment, and lifestyle
for each person.10 Digital health tools are key
enablers of precision medicine. The World
Economic Forum (WEF) Precision Medicine
Initiative operates in the context of enabling
global public–private co-operation and
committing to developing principles and
frameworks that accelerate the application of
science and technology for global public interest,
whilst also mitigating for any potential risks of
new personalised medicine applications in
genomics or big data.11
The Initiative focusses on two exemplar
implementation domains: rare diseases and
cancer. In order to realise the full potential of
precision medicine (including related digital
health approaches), substantial economic,
regulatory, social, and technical challenges to
its broad implementation must be overcome.
Those identified through the WEF include:
1) generating sucient evidence; 2) tackling
data sharing and infrastructure challenges;
3) reshaping the regulatory environment; 4)
adoption of genomic information from research
into clinical care; 5) economics of precision
medicine; 6) creating payment models involving
the gains and risks shared along the value chain;
and 7) attaining greater patient and clinician
engagement and trust. The WEF supports
pilot projects and other initiatives to address,
and hopefully relieve, these bottlenecks.
One such project is Lyfe Languages.12 Lyfe
Languages is empowering and retaining
Indigenous languages, creating more connected
communities, and supporting equitable
advances in digital healthcare. It is a community
engaged and co-designed initiative to deliver
Indigenous language translations of the lingua
franca of precision phenotyping (the Human
Phenotype Ontology [HPO]). Through these
HPO translations, Lyfe Languages digitises and
makes computer-readable descriptions of a
condition’s manifestations (the phenotype)
that are provided directly in an individual’s own
Indigenous language.
Capturing Phenotype Through the Life
and Health System Journey
In medicine, phenotype is a deviation from
normal form, function, or behaviour. Phenotype
can also be thought of as the voice of the patient
and the clinicians describing that patient’s
condition, statically and dynamically. Tools such
as Phenotips,13 Patient Archive,14 and Dx2915
have been developed to facilitate phenotyping,
primarily for diagnostic support for rare diseases.
Another example is Track.health,16 which delivers
approaches to measure, monitor, and track a
patient’s journey within the health system, from
start to finish.
Primary Care
A patient’s medical journey starts and is often
housed in primary care. As such, digital health
integration within and between primary and
specialist care is critical; this is especially true for
complex conditions like rare diseases. The UK
National Health Service (NHS) Long Term Plan
states that every patient will be able to access
a digital-first primary care oer by 2023/2024.17
This, and other primary care initiatives, will need
to embrace the challenges and opportunities of
caring for people with rare diseases. The norm for
people with rare diseases carrying large binders
with their medical history and past appointment
documentation in paper records can be
significantly alleviated by a digital approach.
Other markers to embrace in digital health for
rare diseases are: the proposed Innovative
Medicines Initiative (IMI) call for newborn
screening and digital health tools;18 conferences
that focus on digital health and rare diseases,
such as the World Orphan Drug Congress19 and
multiple other digital health initiatives for rare
diseases launched by various pharmaceutical
companies; and the IMI digital collaboration on
rare diseases in Germany.20
COMMON THEMES AND NEEDS
Amongst the various rare diseases digital
health initiatives there are common themes
and requirements. Some of these include: 1) the
need for patient engagement and co-design; 2)
developing and implementing global technology
standards in genotyping, phenotyping (e.g.,
Phenopackets,21 a developing open standard for

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sharing disease and phenotype information),
and diagnostic coding (e.g., ORPHAcodes22;
“The beginning of wisdom is to call things by
their proper name”);23 3) interoperability,
including avoiding ‘supersiloes’ of patient and
clinical/health system data; 4) a focus on equity
and tools that can be employed in low-resource
environments; 5) real-world data and patient-
centred metrics; and 6) global connectivity
that can be adapted to suit jurisdictional
requirements. Fortunately, the rare diseases
community is already heavily invested in many
of these elements and is often at the forefront of
addressing these issues.
WHY DIGIT-ALL?
Rare diseases can cross all medical specialties,
across all the lifespan, all aspects of life, and all
of the globe. Serving the unmet needs of people
living with rare diseases requires all of us. All of
the various stakeholders can be digitally
connected for more timely, scalable,
and sustainable digital health change. It also
requires a focus that draws upon and empowers
all of the community. Time and time again,
discoveries in the rare diseases domain are
translated to added benefits for people with
more common disorders.24 For instance, one in
two new medicines come from rare diseases
research; for example, the cholesterol-lowering
drugs, statins, are being developed as a result
of researching the rare disease, familial
hypercholesterolaemia.24 Specific digital health
examples of solutions generated for rare diseases
that have then been adapted to serve more
common diseases include the pivot of Lyfe
Languages from an initial focus on rare diseases
to subsequently include the development of
resources for novel coronavirus disease-2019
(COVID-19) and immunodeficiency; and the
development of the COVID-19 symptom tracker,
Covidaware.me,25 which is based on the rare
diseases patient-facing knowledge aggregator
rareaware.me.26 Serving the digital health needs
for people living with rare diseases will benefit
all of us.
CONCLUSION
Rare diseases present a global health challenge
with high unmet need. Serving this need will
provide opportunities to develop solutions for
both rare and common diseases. The context of
the challenges and the opportunities continue to
evolve, and this is particularly evident in the field
of digital health.

EMJ • September 2020 EMJ
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