HVP Country Node Development Workshop

Human Variome Project
Country Node Development Workshop

Timothy D. Smith
tim@variome.org
@tim_d_smith

Purpose of Today

• An interactive discussion about HVP Country Nodes
– What they are

– What they do

– How they do it

• Get some feedback from you on what Country Nodes need to be
– I’ll be putting you on the spot at certain points

• Hopefully inspire some of you to start a Node in your own
Country

Outline

• How to initiate an HVP Country Node

• The role of the Node within the country

• Genetics Capacity within the country or region

• Data Collection: who, what, where and how

• Ethical issues, Access policies and Data Ownership

• Data Model

Here’s my problem

• There is no “official” definition of what a Country Node is
– We’re not quite there yet

• No “instruction manual” for how to build one
– Not yet, anyway

Working Definition

An HVP Country Node is an electronic repository of information on genetic variations discovered in patients residing in a
specific country or belonging to a specific population. Ideally the repository contains information on genetic variations
discovered during both routine diagnostic testing and during research. The repository is managed locally by a committee or
organisation that has sufficient representation of stakeholder groups and the backing or support of the country’s human
genetics society or similar professional body. This committee would be responsible for ensuring the sustainability of the
repository and compliance with local laws, regulations and ethics requirements, as well as determining policies for the
repository (e.g. data access policy, data retention policy, curation policy, etc.) The government need not be directly involved
in the operation or financing of the repository, although such involvement is desirable. At the very least, the Ministry of
Health should be aware of the Node, its operations, benefits to the local health system and its relationship to the
international Human Variome Project. The minimum level of information that should be collected on each variant is that
described in AlAama et al. (2011) and the repository includes information on variants considered to be non-pathogenic as
well as those affecting function (or pathogenic). In addition, the repository should capture all instances of each variation that
are reported, not just the first case.

• From R05-2012: HVP Country Nodes: a partial definition-A report of the Country Node Development Workshop, Paris,
2012 available at http://www.humanvariomeproject.org/

It’s actually pretty simple
“An HVP Country Node is an
electronic repository of
information on genetic
variations discovered in patients
residing in a specific country or
belonging to a specific
population.”

“Ideally the repository contains
information on genetic
variations discovered during
both routine diagnostic testing
and during research.”

It’s actually pretty simple

• Repositories of variation
within a country
• Service with in-country
benefits
– Diagnostic labs
– Clinics
– Policy making and healthcare
delivery planning
– Registries?
• Plays a part in global
collection efforts

Global Collection Architecture

An Organisation

“The repository is managed locally by a committee or organisation
that has sufficient representation of stakeholder groups and the
backing or support of the country’s human genetics society or
similar professional body.”

• The first step in establishing a Country Node is not to build the
database, but to build the organisation

An Organisation

• Need to decide what that organisation looks like
– A local issue

• Must be suitably representative
– All stakeholder groups

• What does this organisation do?
– Will determine what the organisation looks like.

“This [organisation] would be responsible for ensuring the
sustainability of the repository and compliance with local
laws, regulations and ethics requirements, as well as determining
policies for the repository (e.g. data access policy, data retention
policy, curation policy, etc.)”

Decisions to make - establishment

• How the development and operation of the Node will be funded;

• Where the Node will collect data from and how collection will be
achieved;

• What information the Node will collect on each variant; and

• How the collected data will be made available and to whom.

Decisions to make - running

• How operational and managerial decisions will be handled during
the development and continuing operations of the Node;

A robust and representative organisation is required to make these
decisions.

Organisation Types

• Consortium of interested individuals

• University Department

• Human Genetics Society

• Government

• Other

Stakeholders

• Diagnostic laboratories
• Medical geneticists
• Genetic Counsellors
• Researchers
• Ethicists
• Officials from the Ministry of Health and Ministry of Science and Technology
• Genetics societies
• Professional Bodies in charge of certifying labs and medical geneticists
• Patients

Funding & Sustainability

• The funding requirements of the Node fall in to three categories:
– supporting the organisational framework in an ongoing fashion;

– maintaining the operations of the technical systems and infrastructure;
and

– developing new technical systems and infrastructure in response to user
needs.

Funding & Sustainability

• Organisational component most likely to be the highest recurring
cost:
• Recurring technical costs are generally low
• Most likely sources of funds to support organisational
framework:
– Government
– University
– Professional society

Human Variome Project ICO

• We can help…
– Human Variome Project/China Country Development Programme
– Access to the economic and public health evidence for the importance of
HVP Country Nodes;
– Provide assistance to local organisations in their efforts to generate funds;
and
– Work with UNESCO and WHO to improve the knowledge of genetic
disorders and their economic and public health impacts within the science
and health ministries of member states.

Make Initial
Initiation Decisions
Identify Funding
stakeholders Data
Hold a Collection
meeting Data Model
Build an
organisation

Role of the Node

• Service for diagnostic laboratories

• Service for clinicians/genetic counsellors

• Service for medical researchers

• Source of data for the Human Variome Project

• Source of statistics for health service delivery planning

Role of the Node

• driving activity around medical genetics and genomics
– Education – public, CME, etc.

– ELSI

– public funding of genetic testing and genetic health care services

– submission to databases as part of the licensing requirements of
diagnostic laboratories

• act as a “spokesperson” for the Human Variome Project within
the country on issues of importance to the international Project.

• Decide on the role of the Node early, as every choice that needs
to be made will be informed by this decision.

Make Initial
Initiation Decisions
Identify Role of the
stakeholders Node
Hold a
meeting • Funding
Build an • Data Collection
organisation • Data Model

Genetics Capacity

• What tests are available?

• Where are these tests performed?

• What data is generated during these tests?

• What data is shared?
– Locally, nationally, internationally

• Who pays for the tests?

• How will things change in 1, 5, 10 years?

Genetics Capacity

• The Node will need to know all this
– Or, at the very least, be able to find the answers

• The Human Variome Project would like to know this information
as well
– Currently compiling the HVP Country Node Baseline Report

• Capacity will shape what role the Node performs

Appreciate Make Initial
Initiation Capacity Decisions
Identify Survey labs & Role of the
stakeholders clinics Node
Hold a
meeting • Funding
• Data Collection
Build an • Data Model
organisation

Where data comes from

• Molecular data
– Labs – Research and/or Diagnostic

– Clinics/Genetic Counsellors

– Literature

• Clinical Data
– Labs

– Clinics/Genetic Counsellors

– Patients (Registries)

Data Types

• Classified variants

• Unclassified variants

• Benign variants

• NGS/Incidental findings

• Negative results

Depends on…

• Ethical, legal and social restrictions (difficult to change)
– Government/regulatory bodies

– Professional codes of practice

• What data sources are willing to share (political)

• What data is able to be collected (technical)

• How useful the data will be to the end-users of the system (non-
negotiable)

How will collection be achieved

• Technical
– Electronic or Paper

– Manual or automatic

• Process
– At what point in the pipeline

• Do collection activities differ by data source category

ELSI

The Organisation operating the Node will be responsible for
ensuring the data is collected, stored and used in a manner that
complies with all local ethical, legal and social concerns.

Local organisations are best placed to determine how to do this

Need to develop

• Collection policy

• Collection Agreement

• Access policy

• Data ownership/IP policy
– Public/private labs

Collection Policy/Agreement

• What is collected
– Identifiability issues

– Phenotype

• How is it collected

• How is it stored

• When is it collected

• Why is it collected

Access Policy

• Depends on the role
• Who can access data locally and for what purpose
– Controlled Access?
• What use classes

• Who can access data internationally
• What data can be shared and who with
– This is very important
– specific data elements that must be shared are yet to be specified by the
International Confederation of Countries Advisory Council

Ownership/IP

• Who ‘owns’ the data submitted to a Node?
– The lab or the Node

• Private/commercial labs

– License terms

– Withdrawal from the agreement

• Data already shared internationally

Remember

• The issues of what data sources to collect from, ownership of
data and access rights are interconnected

• Permission to collect from certain sources may only be granted if
the Node agrees to certain access rights and ownership
provisions

• Need to be determined before technical development begins

Make Initial Mature as an
Appreciate
Initiation Decisions Organisation
Capacity
Identify Survey labs & Role of the Data Access
stakeholders clinics Node Policy
Hold a Ownership/IP
meeting • Funding Policy
• Data Collection
Build an • Data Model
organisation Sign up
collection
sources

Data Model

• what data is stored in the database
• how each data element is related to each other element
• what format each element can be stored in
• which elements are mandatory
• how much intervention will be made during and after submission by human
beings to:
– standardise format
– assess data quality
– correct errors
– add additional information or combine records

Curation

• Australia

• No curation

• relies on a combination of automated processes, data model and data
submitters

• only allows submission by registered diagnostic laboratories via software
tools that the Australian Node provides

• Only accepts submissions of data that has been recorded in a pathology
report

this change

• Protein, DNA, RNA level

• Coding DNA or genomic DNA

• rs#

• HGVS Nomenclature

• Old school methods

• Bespoke methods (BIC)

this gene

• HGNC name: MC1R, melanocortin 1 receptor, HGNC:6929
• Synonyms: MSH-R
• OrphaNet ID: ORPHA139778
• OMIM: 155555
• Entrez Gene: 4157
• Sequence Accession: NM_002386
• Chromosomal Location: 16q24.3
• Coordinates: 16:89,984,286 - 89,987,384

means this

• Simple
• Free text
• Coding
– ICD-10 (9)
– SNOMED

• Ontologies
– HPO
– GO
– PATO

• 20,000 genes = 20,000 disorders
• All different

patient X

• Ethical, legal and social issues

• Global context

• Patient ID

• Assigned by LSDB

• Useful?

Data Model

• Human Variome Project
ICCAC will set standard for
minimum content
• Each Node represented on
the Council will have input to
this process

Quality

• Once standards exist you can measure

• Transition from research grade to clinical grade

• These resources ultimately need to be useful as clinical decision
support tools

AlAama et al. (2011)

• Gene Name—described in the form of both the HUGO Nomenclature
Committee approved gene name and a sequence accession number and
version number.
• Variant Name—written as HGVS nomenclature (http://
www.hgvs.org/mutnomen/).
• Pathogenicity—classified as five levels of pathogenicity (see Plon et al., 2008).
• Test date—the date that the results where produced.
• Patient ID—a deidentified code which is unique to a patient.
• Patient Age—the age of the patient when tested.

AlAama et al. (2011)

• Patient Gender.
• Submission date.
• Disease associated with the mutation—if diagnosed.
• Lab Operator ID—a code that identifies the operator who uploaded the data.
• Laboratory Name/ID.
• Country/Region Name/ID—if a regional repository is used.
• Level of consent obtained.
• Can the patient be recontacted for other studies?
• Can clinical and/or molecular data be used for statistical analyses (with options for
local laboratory, country, and/or international)?

Australian Node – Phase 1

• Mandatory • Optional
– Gene Accession # and version – Test Details
– Variant Name (as HGVS • Date of test
nomenclature) • Method
– Pathogenicity Classification • Sample Type
(Plon) • Start
– Date of classification • Stop
– Age (at test)
– Disease
– Misc.
• Sample Stored
• Pedigree Available

Australian Node – Phase 2

• Mandatory • Optional
– Gene Accession # and version – Test Details
– Variant Name (as HGVS • Date of test
nomenclature) • Method (inc. NGS Platform)
– Pathogenicity Classification • Sample Type
(Plon) + justification • Sampling Date
– Date of classification • Start
• Stop
– Disease
– Interpretation Method
– Reason for Test (deviation from standard)
– Predictive – Age (at test)
– Carrier – Misc.
– Diagnostic • Sample Stored

Software & Deployed Infrastructure

• DBMS
– Implements data model

– Allows querying of the data

• User interface
– What the user sees

– Access control

• Collection tools

A Node is a living thing

• All technical and organisational elements will require updating
– Needs change

– Laws change

– Technology changes

– HVP Standards & Guidelines

• Role of the Node Organisation is to manage this change

Mature as an Technical
Appreciate Make Initial
Organisation Development
Initiation Capacity Decisions
Identify Survey labs & Role of the Data Access Data Model
stakeholders clinics Node Policy DBMS
Hold a Ownership/IP UI
meeting •Funding Policy
•Data Collection Collection
Build an •Data Model Tools
organisation Sign up
collection
sources

Help is available

• AlAama, J., Smith, T. D., Lo, A., Howard, H., Kline, A. a, Lange, M., Kaput, J., et al. (2011). Initiating a
Human Variome Project Country Node. Human Mutation, 32(5), 501–6. doi:10.1002/humu.21463
• Cotton, R. G. H., Al Aqeel, A. I., Al-Mulla, F., Carrera, P., Claustres, M., Ekong, R., Hyland, V. J., et al.
(2009). Capturing all disease-causing mutations for clinical and research use: toward an effortless system
for the Human Variome Project. Genetics in Medicine, 11(12), 843–9.
doi:10.1097/GIM.0b013e3181c371c5
• Patrinos, G. P. (2006). National and ethnic mutation databases: recording populations’ genography.
Human Mutation, 27(9), 879–87. doi:10.1002/humu.20376
• Patrinos, G. P., Al Aama, J., Al Aqeel, A., Al-Mulla, F., Borg, J., Devereux, A., Felice, A. E., et al. (2011).
Recommendations for genetic variation data capture in developing countries to ensure a comprehensive
worldwide data collection. Human mutation, 32(1), 2–9. doi:10.1002/humu.21397

Solutions

• HGVS nomenclature
• Open Source DBMS products
– LOVD, UMD, MutBase
– Ethnos, Australian Node

• Minimum Content - recommendations
• Ethics
• Submission Forms
• Forum for discussion, debate, consensus

Australian Node

• HVP Portal (v1.0, r512) - A web application which features the basic interface for browsing
and querying a HVP node.
– Open source – MIT License
– Python/django

• HVP Exporter (v1.0, r512) - Basic HVP exporting tool for laboratories. Features simple GUI
and error checking interface, plug-in architecture for customisation between sites and
common libraries for working with MS Access and MS Excel data sources
– .NET C#, python/ironpython

• HVP Importer (v1.0, r512) - A series of tools and web services that receive, decrypt and
process information by submitting laboratories using the standard transaction XML format
– python

Still work to do

• Minimum content
• Infrastructure to enable sharing
• Attribution
– ELSI
– Incentive for submission

• Phenotype description
– Useful – humans and computers
– Language differences

• Describing ethnicity of patients

HVP Country Node Development Workshop

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