Work Packages

Description of Work

AETIONOMY has 10 academic partners (of which 4 are clinical partners), 2 SMEs and 4 EFPIA partners. The 4 committed partners (UCB; Novartis, SARD & BI), have allocated resources  as well as a substantial financial support  of in-kind contribution over the  entire project. The AETIONOMY project is organised in 5 work packages. Work packages 1, 2, 4 and 5 have been pre-defined in the call text, so that only for WP3 were we free to chose a topic and title which is now called “clinical study”, as this reflects the nature of the clinical validation efforts.

AETIONOMY will run for 5 years as of 1 January 2014 (60 months). The majority of activities dealing with the knowledge base, the disease modelling, the organisation of the data cube, the capturing and representation of expert knowledge, the identification of omics-indices and clinical indices and the main data mining part will all take place within the first 36 months of the project. From the first year on, we will involve the clinical partners in AETIONOMY; initially focusing on gathering their expert knowledge, but from year two onwards they will be recruiting patients. The first testing of identified testable mechanisms will start in year 3 of AETIONOMY.

Work Package 1

All management activities, all legal and organisational aspects of the project and all communications are being dealt with in WP1. This is the WP led by the EFPIA coordinating partner, UCB. The Associate Project Coordinator on the academic side is partner Fraunhofer; both partners have implemented a project management office that jointly takes care of the day-to-day management issues. Both partners have identified project managers that have been working on the project to date.

Summary of progress versus plan since last period
  • Involvement with other research initiatives, especially  EPAD, EMIF-AD, PRECISESADS
  • Organised the IMI session on Neurodegeneration at the AD/PD 2015 conference (Nice)
  • Organised the Pro/Con big data debate session at the CONy 2015 conference (Budapest)
  • Preparation and sucessful execution of the Interim Review (Brussels)
  • Organization of the General Assembly in collaboration with EFPIA partner Novartis focussing on IR requested follow up activities (Barcelona)
  • Presentations of the project and first results at different events (see section 3.2)
Significant achievements since last report
  • Organizing NDD conference symposium at AD/PD 2015 in March 2015
  • Organizing CONy 2015 conference session in March 2015
  • Organizing several workshops for information exchange
  • Generating two further Newsletter issues: The AETIONOMY Knowledge base in July 2015 and the AETIONOMY Legal and Ethical Challenges Sep 2015
  • Preparing and executing the successful Interim Review in Sep 2015
  • Organizing in collaboration with Novartis the General Assembly in Nov 2015

Work Package 2

Work Package 2 deals with all data and knowledge management activities; WP2 is therefore the place where the AETIONOMY knowledge base is being designed, implemented and productively operated. WP2 is led by academic partner University of Luxembourg; the WP is co-led by EFPIA partner Boehringer Ingelheim (BI). As part of the contribution of BI to WP2, a postdoc position working at the interface between WP2 and WP3 will be sponsored at partner Fraunhofer. In addition, as part of the contribution of partner UCB to WP2, data curators are financed at partner Fraunhofer (students supervised by scientists).

Summary of progress versus plan since last period
  • Release of the tranSMART component of the AETIONOMY database
  • Release of the BEL component of the AETIONOMY database
  • Launching of the KB Study Request System (with documentation)
  • Deployment of the REDCap for WP5
  • Release of the first chapter of the AETIONOMY cook book as user guide for new users of the database
  • Implementation of cross-querying capabilities among different tools connected to the AKB: tranSMART (UL) – BEL Networks (SCAI) – apiNATOMY  (UCL);
  • Aqcuisition, manual curation, processing and loading of ICM Parkinson’s Disease study containing 36 samples;
  • Aqcuisition, manual curation, processing and loading of BI Parkinson’s Disease datasets for 3 studies and a total of 89 samples;
  • Aqcuisition, manual curation, processing and loading of IDIBAPS Alzheimer’s Disease study containing 17 samples;
  • Aqcuisition, manual curation, processing and loading of EMC’s image data derived from 57 ADNI subjetcs;
Significant achievements since last report
  • APP specific BEL model for Alzheimer was accepted for publication in “Alzheimer´s & Dementia” (planned for 2015)
  • Development of a communication workflow among different computational infrastructures belonging to the ABK: tranSMART – The Data Warehouse containing various services for model-driven mechanism-identification (based on BEL Maps) – apiNATOMY;
  • Further inclusion of different datasets and samples to the ABK: ICM, IDIBAPS, BI and EMC datasets on PD and AD.
  • Demonstrated that all the diverse datasets can be integrated and analysed within AKB

Work Package 3

WP3 is the work package where all taxonomy construction, knowledge modelling, data- and graph- mining and hypotheses generation will take place. WP3 will also assist in the analysis of clinical data generated in the course of WP5 (clinical study). EFPIA partner UCB will be significantly involved in this work package providing informatics, omics and statistical support and this package will be led by SARD. As part of the contribution of partner BI to WP3, a postdoc position working on disease modeling will be sponsored at partner Fraunhofer.

Summary of progress versus plan since last period
  • Image Processing Team (IPT): Full set up and deployment of the Image Processing Pipeline; Design of an updated DoW for the EMC partner to develop a spatial brain model that bridges the image processing pipeline with the semantic model of brain regions.
  • Clinical Expert Team (CET): Established consistent engagement in the curation workflow to (i) collect and collate clinical correlations with neuroanatomy,  (ii) identify key clinical indices from ADNI and PPMI datasets for clustering analysis by the DMT, and (iii) interpret the results of clustering of clinical data by the DMT;
  • Knowledge Management Team (KMT): Stable development of the ApiNATOMY-driven Clinical Information Management System (CLIMS), and its deployment in support of the collection of knowledge about clinical correlations with neuroanatomy in collaboration with the CET; The addition of brain tract routing calculations to provide hypothesis about subcircuits CNS responsible for the spread of NDD pathology.;
  • Data Mining Team (DMT): The first year enabled collecting lists of well documented lists of SNPs which have been curated this year. This served as a platform to move forward integrating clinical information which occurred during the first six months and is increasing regularly its pace during this period.
  • Following previous work by the KI/UCB/SARD partners, two main path are now followed. Heat diffusion in Graph database (Gordon BALL). The work is currently in progress. The previously collected SNP/haplotyping information was curated by Gordon BALL so that stable basis for Heat diffusion process is ensured. Second path: using the Progressive Parkinson Marker Initiative (PPMI) data (clinical, Imaging/genetics) to perform a stratification of patients on a set of information related to a set of patients.
  • WP3 Co-ordination Team (WCT): Identification of studies and agreement with EFPIA data owners to provide relevant clinical trial data in AD/PD for analysis by the DMT.  Data transfer expected by end of the year. Work of the team is progressing in coordination with other WPs (WP2, WP5 and WP1) to ensure access to clinical trial data.
Significant achievements since last report

The co-ordination between the DMT, KMT and CET to carry out clinical data analysis for ADNI and PPMI datasets. Following these coordination efforts, clustering results on PPMI are presented at the Interim Review (2015/09/29) and at the General Assembly (2015/11/04).

Work Package 4

WP4 contains all activities in the ethical and legal context. Two academic partners (LUH & Alzheimer Europe) and the coordinating EFPIA partner UCB will be involved in this WP; a Legal Ethics Advisory Board (LEAB) will be implemented and coordinated by this WP. In addition to the two academic partners LUH and AE, we are currently incorporating an additional patient representation organisation: the European Brain Council.

(See http://www.europeanbraincouncil.org/)

Summary of progress versus plan since last period
  • Outlining and commencing development of a strategy to confront legal and ethical risks associated with patient stratification together with Alzheimer Europe (AE)
  • Joint legal and ethical workshop of AETIONOMY and PRECISESADS was held in Hannover on June 4th, 2015, developing valuable synergies between the two projects
  •  Installing the initial data protection framework through contractual system of mutually binding agreements between data using and data providing partners (circulated for signing by M15; signed by all partners )
  • Continuously providing legal assistance to WP5 in drafting consent forms for prospective study/ and assisting in the applications to Ethics Committees (ECs)
Significant achievements since last report

Further implementation of the “Code of Practice on Secondary use of medical data in Scientific research projects” in close cooperation with IMI; the Code was identified as a valuable instrument to harmonize approaches during the joint legal and ethical workshop between AETIONOMY and PRECISESADS on June 4th, 2015.

Work Package 5

In WP5, the clinical studies for the validation of the mechanism-based taxonomy are organised. This WP also deals with two scenarios relevant for the SME partners in AETIONOMY: in WP5.4, partner Pharmacoidea will make use of the insights gained into disease mechanisms to identify possible targets for preventive or interventional therapy; in WP5.5 partner Neurorad will test to what extent a routine diagnostic imaging lab can utilize imaging-based indices for patient subgroup identification by means of image analysis. WP5 will be led by partner ICM, and Novartis will be the EFPIA partner lead in this work package. As part of the contribution of partner BI to WP5, a postdoc position working on cohorts will be sponsored at partner Fraunhofer.

There will also be an External Scientific Advisory Board (ESAB) that will receive annual reports from the General Assembly. The ESAB will be the consortium body through which external experts will give their advice and feedback on the main arising issues of the AETIONOMY project and the project’s overall strategy and progress.

The main goals of the ESAB will be:

  • Providing requirements and feedback to the project’s objectives and progress.
  • Monitoring the main milestones of the project, updating its feedback, and providing the necessary inputs for guiding the project’s research and activities towards the achievement of the project’s main objectives.
  • Providing a final feedback on results evaluation and expectations for future evolution.
Summary of progress versus plan since last period

 

  • Transcriptomics (PD patients) and microRNA (PD + AD patients) data generated, biomarker data from AD patients generated. All these data are available to AETIONOMY consortium.
  •  Full protocol and ICFs have been finalized and reviewed by Alzheimer Europe and WP4 to provide advice in terms of ethics.
  • Regulatory and ethical submissions of the protocol in France have been achieved on the 11th of March 2015. Approvals obtained in May 2015.
  • Ethical submission of the protocol in Germany have been achieved on the 28th of October 2015. Approvals obtained on the 21st of December 2015.
  • Ethical submission of the protocol in Sweden have been achieved on the 4th of November 2015. Approvals obtained on the 25th of November 2015.
  • Since beginning of September 2015, subjects's recruitment has started at ICM (France).
  • 4 mechanism-based hypotheses with their corresponding surrogates to stratify AD and PD patients have been proposed by WP5 partners to be validated in the AETIONOMY clinical study.
  • PharmacoIdea has exploited the interaction of the syndecan (SDC) family of proteoglycans with Apolipoprotein E (ApoE), a glycoprotein with an emerging role in neurodegeneration.
  • Neurorad began the recruitments of AD patients (n=4) and healthy volunteers (n=8) for the generation of the neuro-imaging gold standard. New publications based on research funded by AETIONOMY are currently under review or have been published:
  • Nonlinear cerebral atrophy patterns across the Alzheimer’s disease continuum studied by the AD CSF Index: Impact of APOE4 genotype.
    Gispert JD et al. (Accepted) - IDIBAPS.
  • Informants' perception of subjective cognitive decline helps to discriminate preclinical Alzheimer's disease from normal aging.
    ValecH N et al. (Accepted) - IDIBAPS.
  • Cerebral morphological correlates of CSF YKL-40: adding loss to neurodegeneration. JL Molinuevo et al. (Accepted) - IDIBAPS.
  • White abnormalities track disease progression in PSEN1 autosomal dominant Alzheimer’s disease.
    JL Molinuevo et al. (Accepted) - IDIBAPS.
  • L-Dopa increases a-Synuclein DNA Methylation in Parkinson’s Disease Patients In Vivo and In Vitro, Movement Disorders.
    Schmitt et al. - UKB (U Wuellner).
  • CSF cytokines MCP-1, MIF and TNF-α 
correlate with cognitive dysfunction in MCI. Brosseron F et al. (Submitted) - UKB (M Heneka).

 

Significant achievements since last report

AETIONOMY protocol finalized and approved in France, in Germany and Sweden by regulatory and/or ethical authorities.

The first patients have been recruited in France and Sweden (as of February 2016).

Partners’ publications:

  •  José Luis MOLINUEVO - IDIBAPS (accepted):
    « Nonlinear cerebral atrophy patterns across the Alzheimer’s Disease continuum: Impact of APOE4 genotype »
    « Informants' perception of subjective cognitive decline helps to discriminate preclinical Alzheimer's disease from normal aging »
    « Cerebral morphological correlates of CSF YKL-40: adding loss to neurodegeneration »
    “White abnormalities track disease progression in PSEN1 autosomal dominant Alzheimer’s disease.”

  • Ullrich WUELLNER - UKB (accepted):
    « L-Dopa Increases a-S
    ynuclein DNA Methylation in Parkinson’s Disease Patients In Vivo and In Vitro, Movement Disorders » - Movement Disorders, June 2015.

  • (Submitted): Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic pattern in periperal blood monocytes

  • Michael HENEKA - UKB (submitted):
    « CSF cytokines MCP-1, MIF and TNF-α correlate with cognitive dysfunction in MCI»