Disease registries have become an essential tool for relevant health care stakeholders to deliver improved quality patient outcomes. Unfortunately to date, there are relatively few established national disease registries (Evans et al., 2011, Rubinstein et al., 2010). This situation is exacerbated for rare diseases as there are over 7,000 identified and reported, and no single institution, and in many cases no single country, has sufficient numbers of patients to undertake generalisable clinical and translational research. The geographic spread of patients is a major impediment to recruitment into clinical trials and most rare diseases do not have a specific International Classification of Diseases code, which hampers research that uses existing sources of information (Rubinstein et al., 2010, Schieppati A et al., 2008). Considerable effort has been made to establish national and ethnic mutation databases (NEMDBs) as well as locus-specific databases (Patrinos, 2006, Sinha et al., 2011, http://www.humanvariomeproject.org/).
Although rare diseases have a low prevalence, when taken collectively they equate to approximately 25 million in the US, 30 million in the European Union and 1.2 million in Australia (http://www.eurordis.org/content/what-rare-disease, http://www.rarediseases.org/rare-disease-information, Knight and Senior, 2006, Zurynski et al., 2008, Dawkins et al., 2011). Changing demographics, particularly the ethnic profile changes in any given country due to immigration and inter-racial marriage may contribute to an increase in prevalence of some rare diseases such as thalassaemia (Prior et al., 2004, Streetly et al., 2008) in developed countries.
Diagnostic laboratories currently conduct genetic testing but this is typically undertaken in the absence of coordinated integrated information-based registries. Diagnostic services in any given locale might be expanded to incorporate new allelic variations for a rare disease but the challenge remains on how best to capture and integrate this new information with existing legacy information for improved decision making (Alaama et al., 2011). Additional challenges arise as there are no agreed international vocabularies adopted for characterising rare diseases. This situation culminates in a substantial burden placed on local population health and genetic service delivery (Rubinstein et al., 2010, Ring et al., 2006).
There is world-wide recognition of the urgency to establish Internet-based platforms for rare disease registries. Such platforms would provide critical infrastructure to integrate information from existing rare disease registries, establish registries for patient organizations currently with no registry or for patients with no affiliation to a support group looking to belong to a registry (Rubinstein et al., 2010).
In recent years, much of the drive to create rare disease specific registries is driven by patient advocacy groups (Terry et al., 2011). This represents a new paradigm in which patients are driving the collaborations with both industry and clinical research. For example, Parent Project Australia (PPA),1 a voluntary organisation advocating for patients and families affected by Duchenne and Becker muscular dystrophies (DMD and BMD), recently initiated a nationwide campaign in Australia. PPA sought: i) support for expanded gene sequencing of DMD cases and to identify appropriate patients to enter specific clinical trials; and ii) government funding for the development of a national database of DMD patients which would then feed into a global database managed in Europe.
The PPA campaign was part of an international effort led by TREAT-NMD, a network based in the UK and Europe (http://www.treat-nmd.eu/home.php), which brings together patients and specialists working on treatments for neuromuscular (NMD) disorders. One of the aims of TREAT-NMD is to create a global network of DMD patient registries which will include both clinical information and a description of the exact DNA mutation found in each patient. The aim being that this clinical and gene-based molecular sequence data will be used to accelerate developments of new therapeutic approaches and in particular novel therapies that specifically target the various alterations in the dystrophin gene that cause DMD and the milder BMD variant (Wilton and Fletcher 2008, van Deutekom et al., 2007).
To follow this example through, in Australia, despite several centres being involved in research on, and management of, individuals with DMD, there is insufficient coordination to ensure the translation of new knowledge into improved patient outcomes. Thus diagnosis, treatment and prevention would benefit from a more integrated approach to improve outcomes, increase innovation and decrease costs. Many countries, facing the same issues as Australia have each established a national registry for DMD. These countries are now forming a global network to create national DMD Registries to be able to systematically and more quickly address the significant unmet needs for new therapeutic strategies in DMD. National patient registries in the UK, Europe and the USA have already proven invaluable as enabling tools to a coordinated approach to diagnosis, therapy, research and prevention of disease (http://www.treat-nmd.eu/resources/patient-registries/overview/, Dreyer et al., 2009, Rubinstein et al., 2010). There is a growing awareness of international registries that provide opportunities for children to access new therapies through global clinical trials.
In Australia, Duchenne Foundation Australia, in conjunction with the Muscular Dystrophy Association, the Muscular Dystrophy Foundation, other support groups and affected families, made representations to state and federal politicians and health ministers to establish a national registry. These campaigns lead to the development of the Australian National Duchenne Muscular Dystrophy (ANDMD) Registry to collate clinical and genetic information about this disease. The ANDMD Registry provides means for clinicians and clinical trial sponsors to quickly identify patients suitable for specific studies. It feeds directly into the TREAT-NMD global network of registries, an international effort that has proven effective in improving the health and management of male children with DMD. This development has lead to other registries being developed. These registries can incorporate new clinical tools that provide innovative approaches to link up those living with rare diseases with clinical networks, academia, industry and government agencies in new and exciting partnerships. These linkages have the potential to positively impact public health and service delivery.
This paper describes a new approach to the design of disease registries to ensure access, security, privacy and the need for clinical sites across Australia to be able to access and register patients with clinical and genetic data often arising from different geographical locations. The approach adopted is readily applicable to other diseases and the design adopted would be generic to other domains requiring the capture, integration and subsequent interrogation of disease information (Bellgard and Bellgard, 2012).
The objective of the present study was to develop a national rare disease registry framework for an Australian context. We have adopted a staged approach by concentrating on muscular dystrophy rare diseases in particular starting with Duchenne and Becker muscular dystrophy. The registry requirements were obtained from advocacy groups with the added constraint to ensure that information captured in the Australian DMD registry follow the minimum information capture required though TREAT-NMD (http://www.treat-nmd.eu/resources/patient-registries/overview/). In December 2008 the Clinical, Technical and Ethical Principal Committee (CTEPC) of the Australian Health Ministers' Advisory Council (AHMAC) delegated the Office of Population Health Genomics (OPHG), Department of Health WA, to convene a working group and prepare a report with recommendations for a National Registry, that collated clinical data and the full dystrophin gene sequence data of patients with DMD and BMD. The report identified the detail and information (minimal data sets) required to enable those on the Registry to meet the clinical entry criteria set for international treatment trials. The Office of Population Health Genomics led the development of this report, in collaboration with other jurisdictions and stakeholders, for consideration by CTEPC in mid 2009.
The report recommendations were developed and endorsed by all stakeholders. Stakeholder engagement included paediatric neurologists, clinical geneticists, genetic testing laboratory managers, executive directors of the muscular dystrophy support groups, nominated jurisdictional representatives and DMD opinion leaders across Australia. A number of different modes of professional and support group stakeholder engagement processes were undertaken in developing these recommendations, including small group fora, telephone interviews and targeted consultations on draft documents. All stakeholders supported establishing a National Registry for DMD, and endorsed the Purpose Statement and Objectives. Recommendations were made under the following seven key areas: Registry and Database Architecture, Coordination and Registry Management, Clinical Information, Genetic Testing, Ethics and Consent, Curating Genetic Data and Governance.
The requirements of the national community were to allow both clinicians as well as geneticists to have their own secure access to the same system. In addition, as this is a national registry, there needed to be an additional level of access for workgroups corresponding to different States or groups within States. The data that a clinician from a given State/region views is private compared to the data that a geneticist can access. Existing systems LOVD and UMD-DMD were technically assessed to determine if the multiple-level workgroup functionality existed or could be easily incorporated. However, both these systems do not offer this capability and their implementations did not lend themselves for new feature enhancement. It was concluded that there was a critical need to develop a new system which is open source (http://code.google.com/p/disease-registry/) and the ANDMD registry is located at: https://www.nmdregistry.com.au/dmd. The design is easily customisable to other diseases, and currently there are three further neuromuscular disease registries, Spinal Muscular Atrophy (SMA) Myotonic Dystrophy (DM) and Facioscapulohumeral muscular dystrophy (FSHD) under construction and registries for other rare diseases in the early phases of design. The landing page URL for all established registries can be found at: http://www.nmdregistry.com.au/. A demonstration system is available at: https://ccgapps.com.au/demo-rdr/. The design of the system is now described.
As with most authentication-based systems, the Australian National Duchenne Muscular Dystrophy Registry can be most broadly broken into two sections: the component available to unauthenticated users and the part available to authenticated users.
Only one page of the DMD Registry is available to unauthenticated users: a landing page explaining the aims of the registry and linking to the government and non-profit stakeholders within the project, as seen in Figure 1.
Authenticated users are associated with a particular working group, with access to patient data being restricted solely to patients registered by that working group. Within a working group, the group's curator can further restrict user access to a patient's basic biographical data, clinical results, genetic variation data, or some combination therein depending on the user's speciality — for example, a clinician may only be granted access to a patient's basic data and clinical data, but not his/her genetic data. This fine grained access allows patient privacy to be respected and maintained to the highest possible level by only providing access to the information specifically required for the user to input and maintain patient records within the DMD Registry. However, it also provides a level of functionality that permits the curator to model the access levels assigned to those working with the registry to mirror their responsibilities and security access levels in the clinic, thus providing a seamless authorisation levels within each clinic and across the contributing sites.
The Django framework has a powerful and flexible authentication component. Users are created by the system administrators. Systems administrators also create groups and assign multiple users to these groups. Very specific and targeted rights can then be assigned to the groups and therefore to all the users belonging to the group. Alternatively, users can also be assigned specific permissions for a specific task, individually and without using groups. The access permissions are very finely defined and can allow restricted access to sensitive data. User access is controlled by password and the session timeout is set so the user gets logged off automatically if the session is inactive for a defined period.
The basic biographical data collected for each patient on the DMD Registry is primarily focused on contact information, both for the patient and his/her medical professional, allowing working group curators to efficiently contact the appropriate people when required. Figure 2 shows the scope of the information collected for each patient.
The DMD Registry provides the ability to capture a wide range of clinical results relevant to patients suffering from muscular dystrophy, including the patient's current motor, heart and respiratory function, current treatments including clinical trials, and other family members affected by muscular dystrophy (or known to be non-symptomatic carriers of the dystrophin gene mutation). The forms and registry were designed to conform to the fields and meet the reporting requirements of TREAT-NMD global network of national registries. Figure 3 illustrates the form used to collect this data.
Each patient within the DMD Registry may have one or more genetic variations recorded within his or her record. As Figure 4a shows, the DMD Registry provides scope for recording DNA, RNA and protein variations in the standard nomenclature proposed by (den Dunnen and Antonarakis 2000) and recommended by the Human Genome Variation Society. For users who may be less familiar with the strict syntax of this nomenclature, a form is provided (shown in Fig. 4b) which provides the ability to enter many common types of variation based on a set of simple drop-down controls, rather than needing to enter the sequence variation as is. Furthermore, error checking is performed on the variation as entered, which allows many simple transcription errors to be caught before the incorrect variation is saved in the DMD Registry, as demonstrated by Figure 4c. The approach taken to this design does not permit patients to enter data. Clinicians/curators enter the data with some validation against the standard nomenclature. In addition, the required IT infrastructure to deploy this system can be easily scaled without any impediments.
Design, customisation and uptake of disease registries are central to engagement of key stakeholders including clinicians, clinical units, health services and hospitals, molecular scientists and advocacy groups. The ANDMD Registry represents the new approach to the design of Internet-based disease registries by providing a means for both clinicians and geneticists to have their own secure access to the same system across workgroups corresponding to different states or groups within states.
This ANDMD enables clinicians and clinical trial sponsors to now quickly identify patients suitable for specific studies. The results feed directly into the TREAT-NMD global network of registries, an international effort that has proven effective in improving the health and management of male children with DMD. This opens up the opportunity for Australian DMD patients to participate in clinical trials being undertaken anywhere in the world. Of current relevance are those trials that target specific genetic mutations, such as exon skipping in DMD, as a way to reduce the symptoms and improve quality of life (Wilton and Fletcher 2008).
The ANDMD and other rare disease under development represent the first national disease registries established in Australia. The experience gained from establishing three national registries in Australia and customising one for a New Zealand DMD advocacy group suggests that this implementation would be easily customisable to many other disease registries and in other countries in a multi-language format.
The authors would like to acknowledge the families of those living with Duchenne and Becker muscular dystrophies who first proposed the development of a national registry. In particular, we thank Deb Robins and Pam Bianchi (Duchenne Foundation), Lesley Murphy (Muscular Dystrophy WA) and the executives of the National and State branches and of the Duchenne Foundation, Muscular Dystrophy Foundation and Muscular Dystrophy Association (Australia). This work was supported by the Australian National Duchenne Muscular Dystrophy Registry Advisory Group members, who have helped guide the development of the Registry: A Cairns, D Clark, M Davis, H. Dawkins (Chair & National Curator), D Du Sart, E Faramus, M Farrar, V Hyland, D Jack, H Johnston, P Lamont, L Murphy, K North, H Rayner, D Robins, M Rodrigues, P Rowe, M Ryan; K Sinclair, B Struk, R Susman, P Taylor, S Thompson, L Youngs (Secretariat & National Coordinator), S Yu and to M Buckley. The authors also acknowledge the part funding support of iVEC through its Industry Government Uptake program.