GATHERING AND MANAGING GENOTYPE AND PHENOTYPE

INFORMATION ABOUT RARE DISEASES PATIENTS

Rafael Mendonça

, Pedro Lopes

, Hugo Rocha

, Jorge Oliveira

, Laura Vilarinho

Rosário Santos

and José Luís Oliveira

University of Aveiro, DETI/IEETA, 3810-193 Aveiro, Portugal

Centro de Genética Médica Jacinto Magalhães, INSA, 4099-028 Porto, Portugal

Keywords: Rare diseases, Genetic mutations, Reference centers, LSDB.

Abstract: Information technology is increasingly present in medicine, and is emerging as a crucial tool both in clinical

monitoring and knowledge dissemination, increasing the success rate in diagnosis and subsequently during

treatment. A particular sub-group of diseases are designated rare or orphan due to the small number of

people suffering from these illnesses. They are sometimes disabling, reducing the quality of life of patients

and affect all relatives around them. The aim of this project was to build a Web information system to

support practice and clinical research in rare diseases, and to facilitate the collection of scientific

information, diagnosis, treatment and patient support. Through this system, one can optimize specialized

medical resources, computing resources and data quality, so that the information is available for consulting

and supporting future decisions. This developed system also allows health professionals to share

information that will be important for enhancing the quality and technological advancement in this area of

public health.

1 INTRODUCTION

The European Organization for Rare Diseases

(EURORDIS) estimates that there are approximately

5000 to 8000 rare diseases in Europe, affecting

about 6% to 8% of the population, and 80% of these

cases have a genetic origin. Due to the reduced

incidence of each individual disease, it is difficult

for patients to find support, both at the clinical and

psychologically level (Aymé et al., 2007). Some of

these chronic diseases seriously affect patients’

quality of life and cause serious damage and

disability in social terms.

The existence of a small number of patients for

each rare disease affects the creation of a minimum

number of cases required for appropriate studies

(Schieppati et al., 2008); (Burke, 2002).

The Portuguese National Programme for Rare

Disorders, approved in 2008, strives towards a

concerted system of patient management, which

relies heavily on a platform designed to gather

information from the different health providers, for

this, we have built a Web-based platform to integrate

all this information obtained from studies, in order to

have a database with information about these rare

diseases and patients. It will support a network of

different public entities in the Portuguese health

system, named reference center, which detains a

wealth of data on patients with rare diseases,

composed of multidisciplinary teams and available

resources for the diagnosis, treatment and medical

monitoring of patients. This organizational structure

permits the best procedures to be available,

simplifying processes and minimizing the resources

needed. Those involved in this information system

administer and register/retrieve clinical information

about the studies performed.

Concomitant with the systematic, widespread

collection of patient data, locus-specific databases

(LSDBs) could be generated, which will not only

facilitate the molecular diagnostic service in the

national context, but also contribute to the global

effort of the Human Variome Project (HVP), that

aims to collect, curate and distribute all human

genetic variation affecting health (Kohonen-Corish

et al., 2010); (Patrinos et al., 2011).

423

Mendonça R., Lopes P., Rocha H., Oliveira J., Vilarinho L., Santos R. and Oliveira J..

GATHERING AND MANAGING GENOTYPE AND PHENOTYPE INFORMATION ABOUT RARE DISEASES PATIENTS.

DOI: 10.5220/0003791204230426

In Proceedings of the International Conference on Health Informatics (HEALTHINF-2012), pages 423-426

ISBN: 978-989-8425-88-1

 2012 SCITEPRESS (Science and Technology Publications, Lda.)

2 OVERVIEW

The importance of genetic records in diagnosis and

results of these rare diseases has taken medicine to a

level where research is extremely important to

Databases emerging with information about human

genome such as the HGMD (Human Gene Mutation

Database) (Krawczak et al., 2000). The data are

public and accessible by all the research community,

and it is important to collect and publish this

information in a biomedical application.

Gene mutation databases are dominant in the

area of health care enabling representation of

diseases. However, there is a lack of detail in clinical

information, which indicates the vulnerability of

these patient groups (Schneeweiss et al., 2005). So

there is a need to provide the clinical tools necessary

to register and personalize studies about all rare

diseases. The point of reference in this area has been

the Orphanet, a web platform directed to the general

public, health professionals and patients, to inform

about orphan drugs and rare diseases (Nabarette et

al., 2006).

3 INFORMATION COLLECTION

In scientific communication, it is essential to use

terms transmitting clear and concise medical

information. Many conventions, when known and

used by all, facilitate understanding among users. In

this paper, we highlight the OMIM, Online

Mendelian Inheritance in Man, (Hamosh et al.,

2005) and HGNC, HUGO Gene Nomenclature

Committee (Bruford et al., 2008). The generic

information is obtained building the match between

diseases and corresponding genes of this sources.

This is essential to establish a correct connection and

utilization, eliminating possible errors in data entry

and process simplification.

This information solution presents the user with

a simple way to select and choose the disease and

genes to be studied. It allows the search for disease

groups or by complete name. For instance, in the

Muscular dystrophy group, OMIM presents three

distinct variants: Muscular dystrophy, limb-girdle

type 1A, type 2D and type 2E.

3.1 LSDB

In contrast to general mutation databases, an LSDB

is a repository of genetic sequence variants

associated with an individual gene. Besides the

mutation data, these databases have important

information regarding the gene itself and have been

referred to as knowledge bases. They are usually

used by a group of researchers in collaboration, with

expertise in a particular gene or phenotype, and

provide a valuable tool for analysis of gene

expression and phenotype, both in normal conditions

and disease (Claustres et al., 2002).

Given the need for an LSDB for the registration

of genetic mutations in this application, the system

chosen was an open-source platform LOVD (Leiden

Open Variation Database) (Fokkema et al., 2005), a

solution that can be installed locally and used by

many professionals in this area, which allows

registration of genetic mutations, linking them to

patients who have been diagnosed. It is important to

include this application in this study because it will

allow collection of information about genes and their

variations with the purpose of registering and

visualizing mutations in the genetic code. The

database structure follows the recommendations of

HGVS (Human Genome Variation Society), which

allows the nomenclature used to be generalized

among all users (Fokkema et al., 2011).

4 ARCHITECTURE

The communication between client and server is

performed using the HTTP protocol, using a web

browser to manage users and the reference center

network of this application. This Web-based

platform provides a set of components/services:

patients, genetic mutations, studies, form templates

and administration. The core has three different

tiers: JSPs pages and JavaScript code to

construction/use the forms; the Stripes framework

and Java as the code source of this application; and

the data persistence using JPA (EclipseLink) to

connect to de database server (Figure 1).

Figure 1: Platform architecture.

LSBD

DatabaseServer

HTTP

JPA

Presentation

Tier

Data

Tier

Business

Tier

Genetic

Mutations

Forms

Templates

Administration

StudiesPatients

Services

Client

HEALTHINF 2012 - International Conference on Health Informatics

424

The application is hosted on a Web server in

combination with the necessary LSDB platforms

(LOVD) to store genetic information.

When a reference center is created, the

application provides an initial setup and all the

patients and genes selected as the targets of the

studies are stored. The LOVD platform is

immediately available and configured with all

information needed to start work in analyzing

genetic mutations.

4.1 Data Protection

The main goal of this structure is to protect the

information and permit access only to accredited

members. So this application divides users between

members, when members are in different roles

assigned by the responsible for each reference

center. This approach implies that we have the

master professionals who configure the form

templates and the diseases, and choose the users.

Each reference center has its own independent

data collection and a set of available components;

the application works as a site of the sites.

The authentication used is a simple web platform

when the username and password (encryption in

MD5) are stored in the database. The authentication

between the system and LOVD interface uses

cookies. Every reference center website can access

all patient records, or add a case that does not yet

exist.

5 RESULTS

The application contains generic disease information

taken from a database, available to reference center

members who are able to access such information. In

addition, information is recorded from studies of

patients and this can be screening, diagnosis,

confirmation of diagnosis, treatment and clinical

monitoring.

For better characterization of the different

diseases, it was necessary to construct a forms

engine, which provides the forms so members can

use and later record this information allowing

visualization.

It is important to highlight that these forms can

be configured according to the needs of the studies

and the disease in question. The forms contain the

title, a short description and a set of fields. The

fields can be of different types: textBox, multitext,

selectBox, radioButton or checkBox. With these

fields we aim to respond to the overall needs of form

personalization. This mechanism of construction to

form templates supports functionalities such as

drag-and-drop and sortable, which makes the

construction more intuitive and user-friendly. If the

reference center requires genetic records, it is

possible to connect between the patient and the

genetic records made in their LOVD platform.

So the information collected in all patient studies

can be complemented as well as genetic analysis

carried out by experts trying to solve and create a

standard in each disease, giving support and

diagnosis as accurately as possible.

This application has with baseline a Web front

end, for two different parts of the system: the

management of the centers of reference network;

and healthcare support for rare diseases with an

LOVD platform to connect patients to genetic

results, to collect all clinical information found.

The administrator has permission to initiate the

creation of the reference center and can be an entity

such as a National Health Service, which should

manage the activity of reference centers and can

send invitations to new users of this system.

The patient register is unique and only the user

with access is able to visualize this information and

use these tools. So this unique register permits all

information to be centralized and available for future

decisions, and prevents data replication. Each patient

has a set of the information like studies and genetic

mutations (Figure 2).

Figure 2: User interface using the reference center

platform.

The studies part presents data about medical

progress, treatment, procedures and health

monitoring. This contains the entire history of all

studies made, allowing a specific search for a date or

a diagnosed disease, for example. It also allows

clinical professionals to add a new study, and choose

and collect all the relative information, with the

support of the template forms, and if desired, to

GATHERING AND MANAGING GENOTYPE AND PHENOTYPE INFORMATION ABOUT RARE DISEASES

PATIENTS

425

highlight any associated suspicion or confirmation

of a rare disease.

The genetic mutation part contains all the

variants found and the associated gene, with a link

that connects to the LOVD interface, showing all

registered information about mutations. This

information contains all details about Exon, DNA

change , RNA change or Protein.

6 CONCLUSIONS

Over time, medical records are stored and used

among different healthcare institutions. This

problem is even more acute in rare disease due to the

lack of information about diseases, symptoms,

diagnostics and genetic causes. As such

concentration in a single reference center all this

information is of paramount importance for

physicians, diagnostic labs, patients and their

families and for research proposals.

In this paper we have presented a Web-based

information system that allows gathering and

managing all information about these patients along

their lives – from genotype to phenotype. Through a

common Internet connection, users have access to

information that they can manage according to their

profile in the system and to their role in each study.

It is possible to manage, in an integrated way,

clinical information (patient data, diagnostics,

procedures, …) and genotype data, such as patient

mutations. The platform’s customization allows

configuring the system according to each disease

requirements. The incorporation of LOVD is also a

great asset, considering its wide adoption in the

field, since it can be also used outside our platform

in an independent yet complementary way.

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