Executive summary #
Project rationale and overall objectives of the project
Today, diseases are still defined largely based on the presentation of signs and symptoms, yet while two patients may share the same diagnosis, the underlying causes of their symptoms may be very different. Naturally, this means that a treatment that works in one patient may prove ineffective in another. There is now broad acceptance that a new approach to disease classification is needed; built not on symptomatology but derived from the inherent pathogenic mechanisms of the disease.
AETIONOMY will pave the way towards a new approach to the classification of neurodegenerative diseases focussing on Alzheimer's and Parkinson's diseases, deriving as a result the prototype of a new mechanism-based taxonomy. This will increase the probability of successfully discovering and developing new therapies for neurodegeneration, and thereby increasing patients' chances of receiving treatments that are effective.
Overall deliverables of the project
The AETIONOMY team, through its 5 work packages, is tackling the problem of how to obtain, dynamically organise, structure, integrate and interpret the range of different types of data (ranging from molecular data, to information on symptoms) currently available in the community. We plan to bring new structure to the classification of disease by dissecting the underlying mechanistic/molecular causes of disease, and by bringing clinical evidence to support these mechanistic drivers.
Achieving this is far beyond the scope of any single company or university; the key to AETIONOMY success will be the broad nature of the project consortium, which brings together 18 partners made up of pharmaceutical companies, universities, and patient groups, and has expertise in neurodegenerative diseases, molecular biology, clinical research, research ethics, data modelling and simulation, data standards, and patient engagement in research. In addition, collaborations with EPAD (European Prevention of Alzheimer's Dementia), ADNI (Alzheimer´s Disease Neuroimaging Initiative), and MJJF (Michael J Fox Foundation for Parkinson´s Disease) have been established to increase available data for validation of our candidate mechanisms. And awareness of the approaches will be brought to other related initiatives like GAP (the Global Alzheimer Platform), C-PATH, UK-DP, HBP, TVB, ADAPTED and PHAGO.
AETIONOMY's innovative approach will deliver data, tools and postulated mechanistic hypotheses structured in a way to enable the biomedical community and regulators to direct the development, approval and use of new diagnostic tests and treatments for Alzheimer's and Parkinson's diseases.
After 5 years of work, AETIONOMY will generate the following key deliverables:
1) A publicly accessible knowledge base with inventories of mechanistic hypotheses that form the basis for the prototypic mechanism-based taxonomies for AD and PD. This knowledge base, which combines curated clinical and relevant OMICS-data, disease models for AD and PD and dedicated curation, and analysis and visualisation services.
2) An initial validation of the prototypic, mechanism-based taxonomies and the demonstration that the mechanism-based taxonomy can be used for patient subgroup identification and target/biomarker identification.
3) The mechanism based taxonomy exposed to the academic and biomedical communities (including regulatory authorities) to influence future development of regulatory requirements, the future research landscape, to educate and enable patient organisations and the European citizens funding the project and the political and administrative bodies involved.
AETIONOMY has achieved most of its objectives so far; in particular, a comprehensive selection of candidate mechanisms (the “inventory” of candidate mechanisms in NeuroMMSigDB) has been generated and all relevant data and all relevant knowledge has been curated and re-annotated. A clear strategic focus for the remaining 12 months of the funded period of the project is essential to achieve the key objective of AETIONOMY, namely, to come up with a prototype mechanism-based taxonomy for Alzheimer´s Disease and Parkinson´s Disease and its partial validation in a clinical study.
AETIONOMY will therefore focus on three different key activities:
1) In-silico validation of the candidate mechanisms in NeuroMMSigDB, with a special focus on the seven shortlisted candidate mechanisms. Demonstrating the potential of these candidate mechanisms to identify strata of patients in patient-level data is a pre-requisite for the generation of the mechanism-based taxonomy of neurodegenerative diseases.
2) Wet lab validation of the seven shortlisted candidate mechanisms based on biomarkers representing these mechanisms. A particular challenge here is the link between the readouts in the shortlisted candidate mechanisms and readouts (variables) in patient-level data
3) Implementation of a prototype of the Virtual Dementia Cohort (VDC). The concept of the VDC has raised a lot of discussion in the scientific community, reaching far out beyond the core community of neurodegenerative disease research. AETIONOMY will focus resources and effort on the goal of having a first demonstrable implementation of the VDC published at the end of the funded period of the project.
Adapting to the changing circumstances of the project the coordinators have issued the following statement to ensure coordination across workstreams is emphasised.
“The project office (PO) appreciates the effort to generate the agreed (& mechanism-related) biomarker data from the clinical cohorts (either partner biomaterial banks or the prospective AETIONOMY PD cohort) and looks forward to obtaining the majority of those data by the end of April 2018.The necessity of imposing this deadline is driven by our overarching goal (namely the identification of patient-subgroups that are characterized by identifiable pathophysiology mechanisms), as it is WP3 who will be tasked with the wider integration of polyomic data there is a need to gain access early enough to facilitate the data pre-processing and data analysis tasks (including mechanism-association of patterns found) before our ultimate deadline.
WP3 remains committed to establishing the relationship between our internally derived (WP5) biomarker measurements and those external clinical / biomarker data sets (i.e. ADNI, EMIF-1000, AddNeuroMed, AIBL for AD; PPMI, MAP2PD – as an aside each of these named datasets should be considered as data only, as none of the studies are likely to provide sufficient samples to be integrated into our biomarker workflows).
The PO asks WP5 partners to redouble efforts to provide a "data generation plan", which consists of the complete picture of resource planning (incl. timelines) for the generation of their respective centres’ biomarker data, and the logistics of any sample transfers. This is important both for the planning for subsequent data transfer activities but is also critical for us to get the financial status of the project in line and ensure that budget is appropriately distributed. This description should make explicit whether any further characterization of biomarkers is planned in patient samples outside of the AETIONOMY cohort.
In parallel WP3 is likewise challenged to update the various analyses plans so that the requisite effort can be likewise costed, and naturally the flow of data around the consortium and into the central AKB needs to be managed by UL and Fraunhofer and therefore WP2 needs to appreciate the effort required.
Please note that both, the "data generation plan" and the "data analysis plan" will become part of the DoW in its final version for the last months of AETIONOMY.”
The consequence of this statement will be captured in greater detail in upcoming DoW amendments, but the emphasis here is to ensure accountability and ownership of practical elements of the overall delivery are properly assigned and that there is an element of structure to the planning of the final months of the project.