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This is the author’s final version of the work, as accepted for publication following peer review but without the publisher’s layout or pagination.

The definitive version is available at:

http://dx.doi.org/10.1016/j.hlc.2016.10.019

Napier, K.R., Pang, J., Lamont, L., Walker, C.E., Dawkins, H.J.S., Hunter, A.A., van Bockxmeer, F.M., Watts, G.F. and Bellgard, M.I. (2016) A Web-Based

registry for familial hypercholesterolaemia. Heart, Lung and Circulation, 26 (6). pp. 635-639.

http://researchrepository.murdoch.edu.au/id/eprint/35098/

Copyright: © 2016 Elsevier B.V. on behalf of Australian and New Zealand Society of

Cardiac and Thoracic

It is posted here for your personal use. No further distribution is permitted.

Accepted Manuscript

Title: A Web-Based Registry for FamilialHypercholesterolaemia

Author: Kathryn R Napier Jing Pang Leanne LamontCaroline E Walker Hugh JS Dawkins Adam A Hunter FrankM van Bockxmeer Gerald F Watts Matthew I Bellgard

PII: S1443-9506(16)31693-6DOI: http://dx.doi.org/doi:10.1016/j.hlc.2016.10.019Reference: HLC 2239

To appear in:

Received date: 12-7-2016Revised date: 24-10-2016Accepted date: 30-10-2016

Please cite this article as: Napier KR, Pang J, Lamont L, Walker CE, DawkinsHJS, Hunter AA, Bockxmeer FM, Watts GF, Bellgard MI, A Web-BasedRegistry for Familial Hypercholesterolaemia, Heart, Lung and Circulation (2016),http://dx.doi.org/10.1016/j.hlc.2016.10.019

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A Web-Based Registry for Familial Hypercholesterolaemia

Kathryn R Napier1, Jing Pang2, Leanne Lamont3, Caroline E Walker3, Hugh JS Dawkins1,3,4,5, Adam A Hunter1, Frank M van Bockxmeer6,7, Gerald F Watts2,8,

Matthew I Bellgard1*[d1]

1Centre for Comparative Genomics, Murdoch University, Perth, WA, Australia

2School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

3Office of Population Health Genomics, Public Health Division, Department of Health, Government of Western Australia, Perth, WA, Australia

4Centre for Population Health Research, Curtin University of Technology, Perth, WA, Australia

5School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA, Australia

6Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, WA, Australia

7School of Surgery, University of Western Australia, Perth, WA, Australia

8Lipid Disorders Clinic, Cardiometabolic Service, Royal Perth Hospital, Perth, WA, Australia

*Corresponding author:Prof Matthew BellgardCentre for Comparative Genomics, Murdoch UniversityBuilding 390, West Entrance, Discovery WayMurdoch, WA 6150, Australia

mbellgard@ccg.murdoch.edu.au

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Abstract

Familial hypercholesterolaemia (FH) is the most common and serious monogenic

disorder of lipoprotein metabolism that leads to premature coronary heart disease.

Patients with FH are often under-treated, and many remain undiagnosed. The

deployment of the FH Australasia Network Registry is a crucial component of the

comprehensive model of care for FH, which aims to provide a standardised, high-

quality and cost-effective system of care that is likely to have the highest impact on

patient outcomes. The FH Australasia Network Registry was customised using a

registry framework that is an open source, interoperable system that enables the

efficient customisation and deployment of national and international web-based

disease registries that can be modified dynamically as registry requirements evolve.

The FH Australasia Network Registry can be employed to improve health services for

FH patients across the Australasia-Pacific region, through the collation of data to

facilitate clinical service planning, clinical trials, clinical audits, and to inform clinical

best practice.

Keywords: Disease registry; Familial hypercholesterolaemia; Interoperable; Model of

care; Open source; Registry framework

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Introduction

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a relatively common genetic disorder that is

associated with premature coronary heart disease (CHD) [1, 2]. In Australia, at least

65,000 people are estimated to have FH with the vast majority of cases remaining

undiagnosed, and in many diagnosed cases, patients are receiving inadequate

treatment [1, 3]. A patient registry to store clinical and family data is essential to the

effective provision of services [4-7], and is therefore a vital component of the FH

model of care for Australasia [3] and integrated guidance of care for FH [8]. A recent

global ‘call to arms’ by the European Atherosclerosis Society FH Studies

Collaboration also emphasises the importance of FH registries worldwide [9].

The Registry Framework

Recently, we presented an open source disease Rare Disease Registry Framework

(RDRF), that allows the efficient deployment of web-based registries that can be

modified dynamically as requirements evolve [10, 11]. The RDRF empowers registry

administrators to construct registries with minimal software developer effort, by

allowing users to dynamically create all data elements (DEs) that define a patient

registry and to share DEs across registries. Registries are described in a computer-

readable text file, which allows a registry definition to be imported/exported,

versioned, and stored in a shared accessible environment.

The RDRF takes a conceptual approach to the design and development of

patient registries to ensure access, security, privacy, and to meet the need for

harmonisation across multiple clinical sites in a given country, or internationally. The

RDRF also fulfills the key criteria required for sustainable registry development [12-

15], and continues to evolve since first described by Bellgard et al. [10, 11, 13, 16].

We describe the deployment of the FH Australasia Network Registry utilising

the RDRF. The primary purpose of the FH Australasia Network Registry is to collate

data to facilitate clinical service planning, and to inform clinical best practice [4]. The

registry will also enable research on aggregated data, and the identification of eligible

volunteers for clinical trials.

Materials and Methods

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Governance and access to patient data

The FH Australasia Network Registry is governed by a National Advisory Board

appointed from expert members from Australia and New Zealand of the FH

Australasia Network, which is a subcommittee of the Australasian Atherosclerosis

Society. The National Advisory Board, which has a Chairman and a Custodian

elected by members of the Board, oversees the governance of the registry and is

responsible for all registry activities and reviewing all requests for access to data. All

projects sanctioned by the Board are conditional on approval by a recognised

authoritative body in the relevant jurisdiction in which the investigation will be

undertaken. Access to the registry is co-ordinated by the registry co-ordinator

(assigned by the National Advisory Board) who is responsible for overarching data

curation, cross-site co-ordination, and arranging processes for data extraction. The

registry co-ordinator provides access to the registry through the provision of password

protected user accounts to authorized data curators.

The FH Australasia Network Registry includes individuals diagnosed with

FH, individuals with suspected FH, children of individuals with diagnosed FH, and

undiagnosed family members of individuals diagnosed with or suspected to have FH.

The registry links index patients to family relatives through the Family Linkage and

Patient Relatives modules.

Recruitment to the FH Australasia Network Registry began in January 2015,

co-ordinated through the registry co-ordinator lending support to each jurisdictional

clinical service. Patients with a diagnosis of FH from participating clinics in Australia

and New Zealand were provided with a FH Registry Information and Consent Form

(available from https://fhregistry-international.com/). After providing consent,

patients were registered and assigned to a “working group”, which is their

jurisdictional clinical service. The RDRF has multiple levels of access (Appendix A),

with the ability to assign different users to selected working groups. Only the registry

co-ordinator has administration privileges, and therefore access to patient data from

all jurisdictions.

Requests for access to data by third-parties are regulated through the National

Advisory Board. Provision of de-identified data is subject to approval by a

jurisdiction human research ethics committee, recommendation by the National

Advisory Board, approval of the data custodian (assigned by the National Advisory

Board) and the study objectives being aligned with Registry objectives.

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Ethics Committee and governance approvals were obtained for each clinical

service site prior to registering patients for the registry. There are no costs to

registrants or their family members.

System architecture, registry deployment and security

The FH Australasia Network Registry is web-based and accessed from

https://fhregistry-international.com/. The RDRF is built on top of Django 1.8 (www.

djangoproject.com/), utilising PostgreSQL (www.postgresql.org/), MongoDB

(www.mongodb.org/), HTML, CSS, YAML (www.yaml.org/), Javascript, jQeury

(jquery.com/) and Bootstrap (getbootstrap.com/). The RDRF is typically deployed via

Docker containers (www.docker.com) using uWSGI (uwsgi-docs.readthedocs.org/)

and nginx (nginx.org/). Django provides distinct levels of inbuilt security, including

secure socket layer (SSL) security (encrypts all web traffic to and from the

application), cross-site request forgery (CSRF) checking, login restrictions of all

views, with the RDRF utilising the Django secure package middleware with all

settings enabled by default. The RDRF also stores identifying patient demographic

data in a distinct database to any clinical data (Fig. 1) [11, 13, 16]. The source code

for the RDRF is available at https://github.com/muccg/rdrf.

Capture of patient data

The demographics and clinical information for each patient are captured by the

‘Demographics’ and ‘Consents’ modules and six additional Forms titled Clinical

Data, Medications, Genetic Data, Imaging, Apheresis and Follow Up (Fig. 2).

Currently, all DEs requested by the International FH Consortium are included in the

FH Australasia Network registry (see Appendix B for a detailed list of all current

Data Elements).

New features and enhancements

Several new features have been developed in the RDRF (see Appendix A), including:

i) Dynamic Consent and Validation; Consent sections and questions are now

dynamically defined for each registry, and validation and applicability rules may also

be applied.

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ii) Patient Relatives Module; Each Patient Relative is linked to an Index

Patient through the ‘Patient Relatives Table’, which aides in tracking the results of

cascade family screening.

iii) Family Linkage Module; Aides in viewing all relatives of an Index Patient

and their relationships. It also allows Patient Relatives to be promoted to an index (in

the case an index patient requests to be removed from the registry).

iv) FH Pedigree Module; Collates information on the number of first, second,

and third degree relatives, and allows a file containing a family pedigree to be

uploaded and stored. This section is configured to appear only on the Demographics

Form of Index Patients. There is potential for a pedigree-drawing tool to be developed

and included in the registry at a later date.

Conclusions

The FH Australasia Network Registry provides supporting infrastructure in

four key areas: i) addressing a current gap in the flow of data for measuring the

quality of healthcare; ii) supporting basic research through the provision of high-

quality, de-identified data; iii) enabling geographically equitable access to clinical

trials; and iv) promulgating information about best practice and care services [4]. The

valuable data captured by this registry will inform research, clinical decision making,

educational programmes, and ultimately improve the quality of care for FH patients.

Acknowledgments

Development of the FH Australasia Network Registry was made possible through

development grants from the Office of Population Health Genomics, Government of

Western Australia and the FH Australasia Network of the Australian Atherosclerosis

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Society. The Australian Atherosclerosis Society supports the FH Australasia Network

and has received grants in-aid from Sanofi, Amgen and MSD Australia. The authors

gratefully acknowledge the combined support-in-part funding for this work. This also

includes the RD-Connect-European Union Seventh Framework Programme

(FP7/2007–2013 program HEALTH. 2012.2. 1.1-1-C) under grant agreement number

305444: RD Connect: An integrated platform connecting databases, registries,

biobanks and clinical bioinformatics for rare disease research, the financial support of

the Australian National Health and Medical Research Council (APP1055319) under

the NHMRC–European Union Collaborative Research Grants scheme, and the

Wellcome Trust [REF 104746]. GFW has received honoraria for lectures, research

studies or scientific advisory boards from Merck Sharp and Dohme, Novartis, Kowa,

Amgen, Sanofi and Regeneron.

The authors wish to thank the following key opinion leaders and primary

investigators for their involvement in the development of the FH Australasia Network

Registry; David R Sullivan, Karam Kostner, Warrick Bishop, Peter M George,

Richard C O’Brien, Peter M Clifton, Stephen J Nicholls, Ian Hamilton-Craig,

Timothy R Bates, Damon A Bell, John R Burnett, David M Colquhoun, David L

Hare, Edward Janus, Michael P Metz, Jacqueline DM Ryan, Leon Simons, and

Shubha Srinivasan. The authors also acknowledge software development provided by

Lee Render and Maciej Radochonski. The authors wish to acknowledge the FH

Australasia Network and the Australian Atherosclerosis Society for their partnership

in the FH Australasia Network Registry.

The FH Australasia Network Registry meets the requirements of the National

Statement of Ethical Conduct in Human Research and has approval from the Royal

Perth Hospital Human Research Ethics Committee (REG 13-148), the Department of

Health WA Human Research Ethics Committee (2013/79), the Sydney Local Health

District Ethics Review Committee (HREC/14/RPAH/173), the Women's and

Children's Health Network Human Research Ethics Committee

(HREC/15/WCHN/156), and the Murdoch University Human Research Ethics

Committee (2016/153).

Figure Legends

Figure 1: The Rare Disease Registry Framework: Data is encrypted both at rest and in

transit and stored in PostgreSQL and MongoDB. Demographic data is stored in a

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separate and distinct database to phenotypic and clinical data. All web traffic to and

from the application is encrypted. Multi-level access and configurable permissions

allow different user groups to log into the registry.

Figure 2: Modular structure and functions of the FH Australasia Network Registry.

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