On behalf of the DDMoRe consortium

What purpose is the DDMoRe library serving?

WCoP 2016 - Brisbane

Zinnia P Parra-Guillen and Iñaki F. Trocóniz

School of Pharmacy, University of Navarra, Pamplona, Spain

•Background

•Intention & key features

•Structure

•Contents

•Functionalities

•Submission guidelines

Outline

Current bottlenecks in applying efficiently MID3 include complexity of the structural and statistical sub-models, coding & dataset arrangement

• Drug and disease models available in literature are often difficult to re-implement

• To date no public-available drug and disease model libraries exist except for recent private initiatives

To fulfil part of the daily requirements in pharmacometrics an efficient repository needs to be far beyond a simple warehouse

Background

Model library is one of the key products of DDMoRe

• It is an open, public-available and free-to-use cloud-based model library for drug and disease models

• Currently under development and which will be further supported by the DDMoRe foundation

DDMoRe model library provides a platform to:

(i) store and share models in a secure and version control manner,

(ii) friendly display key model features (e.g. structure, parameters)

(iii) annotate models based on ontology standards and metadata

(iv) connect to external databases

Intention & key features

Structure and Functionalities (overview)

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Private Instance Public instance

No login restrictions Search for different public models Model & Language exploration Download

Login account Model submission Share and store own models Tracking of different versions

Model publication

Certification

Contents

Items Description

Models Published models mainly in diabetes, oncology, other diseases as CNS and anti-infectives , safety, and others

Files Minimal requirements, automatically checked when submitting a model • Executable model code • Example of real or dummy dataset guiding data organization • Command text file illustrating how to execute the model • Set of annotations describing the modelling exercise and context of use • Output files (if the model is executable)

Language MDL and PharmML, the two standard languages developed by the DDMoRe consortium to enable interoperability Models provided in original target code

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78 models available*

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* Most of the current models have been published in peer review journals

Functionalities overview

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Functionality Description

Access http://repository.ddmore.eu/

Browsing/Searching • Fully searchable engine reinforced by the used of metadata

• Relies on submitter provided information

Model exploration Optimal display when PharmML is used Access to version history Download

Connection to other DDMoRe products

Possibility to execute the model on different softwares

An example

An example

Model annotation

Ensures that a relevant description of every model is collected

Enables queries for models based on key model features

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Free text

Metadata

Overview (I)

Overview (II)

Model definition

Plus: • Initial conditions • Variability model • Covariate model • Observational model

Estimation Steps

Mandatory files

• Executable_Mielosupression.xml

Additional files

• Output_simulated_SEE_NONMEM.lst

• Neutrophils_VPC.tiff

• Simulated_WBC_plac_ddmore.csv

• Model_Accomodation.txt

• Neutrophils time profiles.tiff

• Executable_Mielosupression.mdl

• Command.txt

• Output_simulated_SSE_Monolix.txt

Files

Mandatory files

• Executable_Mielosupression.xml

Additional files

• Output_simulated_SEE_NONMEM.lst

• Neutrophils_VPC.tiff

• Simulated_WBC_plac_ddmore.csv

• Model_Accomodation.txt

• Neutrophils time profiles.tiff

• Executable_Mielosupression.mdl

• Command.txt

• Output_simulated_SSE_Monolix.txt

Files

Mandatory files

• Executable_Mielosupression.xml

Additional files

• Output_simulated_SEE_NONMEM.lst

• Neutrophils_VPC.tiff

• Simulated_WBC_plac_ddmore.csv

• Model_Accomodation.txt

• Neutrophils time profiles.tiff

• Executable_Mielosupression.mdl

• Command.txt

• Output_simulated_SSE_Monolix.txt

Files

Mandatory files

• Executable_Mielosupression.xml

Additional files

• Output_simulated_SEE_NONMEM.lst

• Neutrophils_VPC.tiff

• Simulated_WBC_plac_ddmore.csv

• Model_Accomodation.txt

• Neutrophils time profiles.tiff

• Executable_Mielosupression.mdl

• Command.txt

• Output_simulated_SSE_Monolix.txt

Files

Reproduce results using the DDMoRe Interoperability Framework

Dataset example

History

Not all models have associated the PharmML code

Not all models have associated the PharmML code

Private model entry Default instance for any model uploaded, visible to submitter and those who he/she shared the model to. Need a repository account.

Public instance of model repository Transfer of model to public Instance upon user request (via "Publish" button) For models fulfilling minimal requirements only. Visible to anyone. No need for a repository account.

Private instance

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Submitter

Submitter

Upload/submit

Publish Required files

with description

Required files with

description

Annotations

Required files with

description

Annotations

Submission Guidelines

Ground submission rules

• Quality depends solely on submitters

• Any models can be shared if fulfilling minimal requirements

• Discrepancy from publication needs to be documented

• Simulated data are needed to understand data structure and execute the models

• Output files are needed to check the model is executable and uncertainty on parameters

Terms of agreement

• Any submission is linked to a submitter name

• By publishing the submitter accepts to share model in the public domain

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Minimal requirements to publish

Technical: submitter provides relevant information for the scenario chosen

• Model code (MDL/PharmML or original) with description

• Dataset with description

• Output files with description

• Additional files like command for code execution

• Model annotation (e.g. author, disease area, context of use, ...)

Scientific: No requirements per se

• DDMoRe relies on the scientific community to fill the repository with relevant content

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Take home message (1/2)

Value How DDMoRe delivered this

Shared knowledge The repository holds (n>70) a diversity of simple and complex searchable models covering e.g. oncology, diabetes, CNS, infectious disease and safety

Scientific quality

Models are published based on annotation standards

Controlled environment Secure and sustained access to models. Standardized submission process.

Visibility DDMoRe repository content directly readable without login / easily found in google

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http://www.ddmore.eu/tutorial/tutorials-model-repository

Take home message (2/2) It has been funded by EU for the world-wide modeling

community….

…. we can all benefit from the DDMoRe repository only if we continuously fill it with relevant models ….

(think about all the models you published, can you share at least one every 5 years? How difficult would that be?)

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Stephan Benay, Mihai Glont, Celine Sarr, Zinnia Parra-Guillén, Siv Jönsson

Modelling review group

WP1 participants

DDMoRe consortium

Acknowledgments

Back-up slides

Submission Guidelines

Four different scenarios to identify

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Private model entry Model in public domain

Model certification concept

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Submitter

Submitter

Upload/submit

Publish

Submitter

Required files with

description

Required files with

description

Annotations

Required files with

description

Annotations

Required files with

description

Annotations

DDMoRe Certification

Certification request

MRG1) Review

1) Modeling review group

On behalf of the DDMoRe consortium

Annotate the

model