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WP 25: Vascular Health

Lead: Atticus Hainsworth (St George’s University London, SGUL)

Aim: To exploit the Data Portal to evaluate cerebrovascular risk from genes and modifiable multi-comorbidities, and quantify their impact via MRI, to optimise interventional trials design.

Start Date: Jan 21                                                                                                                                                                                                                     End Date: Dec 25

Team: SM Allan (Manchester), P Bath (Nottingham), T Blackburn (TP Ventures Ltd), Z Cader (Oxford), R Carare (Southampton), K Horsburgh (Edinburgh), RN Kalaria (Newcastle), S Love (Bristol), CE MacKay (Oxford), HS Markus (Cambridge), JT O’Brien (Cambridge), J Pickett (UK) Alzheimer’s Society), TJ Quinn (Glasgow), RM Touyz (Glasgow), JM Wardlaw (Edinburgh), D Werring (London), S Williams (London).

 

Overall objectives: To exploit the Data Portal to evaluate cerebrovascular risk from genes and modifiable multi-comorbidities, and quantify their impact via MRI, to optimise interventional trials design. Work Package 25a will quantify brain vascular lesion progression via DPUK2’s Data Portal and test the relationships of vascular and dementia risk factors with change in SVD related lesions, (WMH, lacunes, microbleeds PVS), DTI parameters and composite metrics (brain age, brain health index). Work Package 25b will perform sub-analyses of candidate genes.  Work Package 25c will perform sub-analyses of mechanistic pathways.

 

Background: Work Package 25 uses the Data Portal (Work Package 21) to generate mechanistic hypotheses from big-data to optimise the design of interventional studies. Results will be used to develop proposals for an interventional experimental programme. Vascular disease increases steeply with age and combines with neurodegenerative pathologies (notably, AD) to accelerate cognitive decline27-29. Recent trials (SPRINT, INFINITY, FINGER, Ontario Health Registry, and ADNI) suggest that addressing cardiovascular risk slows cognitive decline. The most prevalent vascular cause of cognitive impairment is cerebral small vessel disease (SVD)30 seen as white matter hyperintensities (WMH), lacunes, microbleeds and enlarged perivascular spaces28,31. The potential for reducing vascular cognitive impairment is rapidly emerging33. We will conduct a multi-cohort, multi-modal analysis to identify tractable targets for risk stratified groups. Using UK Biobank (UKB) as a core data set, we will link with other DPUK cohorts and search other databases, e g JPND Harness and MetaCohorts, for relevant data. We will use the Data Portal as a transparent repository for data access at a consortium level. UKB is ideal for this work, combining imaging with diverse and detailed antecedent data32. UKB is funded to include n=100k brain and cardiac MRI scans (n=35k to date) and n=10k repeat scans (1,000 scans to date).

This programme will deliver evidence for stratifying vascular risk and identify pharmacologically tractable vascular targets related to dementia. We will share novel imaging measures, via the Data Portal; working alongside Work Package 22 to prepare pipelines. This exemplar positions DPUK to increase industry interest in vascular treatments for dementia with a view to optimise future research partnerships.

Objective 1: Perform analysis of PVS and vascular lesion burden using UK Biobank and other data sources (work package 25a)

Deliverable 1: Recruit Postdoctoral Research Assistant

Deliverable 2: Obtain data from UK Biobank

Deliverable 3: Identify and obtain appropriate additional data sources

Deliverable 4: Complete analysis of vascular lesion burden

Deliverable 5: Image analysis of data sample for peri-vascular spaces

Deliverable 6: Statistical analysis of data

Deliverable 7: Share resultant dataset using the DPUK data portal

Deliverable 8: Findings from the analyses shared with the Vascular EM team

 

Objective 2: Define drug targets using Mendelian Randomisation (work package 25b)

Deliverable 9: Recruit Postdoctoral Research Assistant

Deliverable 10: Obtain data from UK Biobank

Deliverable 11: Identify and obtain appropriate additional data sources

Deliverable 12: Incorporate data from work package 5a

Deliverable 13: Complete initial Mendelian Randomisation studies looking at conventional risk factors and risk of MRI-defined small vessel disease

Deliverable 14: Complete initial Mendelian Randomisation studies looking at novel risk factors and risk of MRI-defined small vessel disease

Deliverable 15: Statistical analysis of data

Deliverable 16: Share resultant dataset using the DPUK data portal

Deliverable 17: Findings from the analyses shared with the Vascular EM team

 

Objective 3: Define drug targets using analysis of cardiovascular disease and drug history (work package 25c)

Deliverable 18: Recruit Clinical Research fellow

Deliverable 19: Obtain and analyse data from UK Biobank

Deliverable 20: Identify and obtain appropriate additional data sources

Deliverable 21: Incorporate data from work packages 5a and 5b

Deliverable 22: Complete initial scoping analyses

Deliverable 23: Choose drug targets using Delphi consensus

Deliverable 24: Complete analysis on data portal

Deliverable 25: Publish a publication on analyses conducted

Deliverable 26: Expert Consensus Panel formed

Deliverable 27: Share resultant dataset using the DPUK data portal

Deliverable 28: Consensus meeting held including input from industry partners and Clinical Trials work package

Deliverable 29: Findings from the analyses shared with the Vascular EM team

 

Objective 4: Collation of research across Vascular Health work packages

Deliverable 30: Vascular EM team to assess progress and focus subsequent directions

Deliverable 31: Vascular EM team to discuss progress with industry partners and other DPUK themes

Deliverable 32: Annual review of milestones by Work Package leads

Deliverable 33: Future studies developed and refined

Deliverable 34: DRI-DPUK Vascular theme interface maintained

 

Objective 5: DPUK/MRC project reporting

Deliverable 35: Quarterly reporting

Deliverable 36: Annual reporting

Deliverable 37: End report

Deliverable 38: Financial reporting

 

 

Objective 1: Perform analysis of PVS and vascular lesion burden using UK Biobank and other data sources (work package 25a)

Milestone

Description

How and who

Outcomes

Dates

Deliverable 1: Recruit Postdoctoral Research Assistant

M1.1.1

Recruit a Postdoctoral Research Assistant

Advertise and appoint to post (JW)

Research Assistant employed

Jul-21

Deliverable 2: Obtain data from UK Biobank

M1.2.1

Submit request and receive data from UK Biobank

Apply, and receive data (JW, RA)

UK Biobank data downloaded

Nov-21

Deliverable 3: Identify and obtain appropriate additional data sources

M1.3.1

Identify appropriate additional data sources

Review datasets available

Additional datasets identified

Sep-21

M1.3.2

Submit request and receive data from additional data sources

Apply, and receive data (JW, RA)

Additional datasets downloaded

Oct-21

Deliverable 4: Complete analysis of vascular lesion burden

M1.4.1

Clean the downloaded datasets

Clean data (RA)

Data cleaned

Dec-21

M1.4.2

Collate the cleaned datasets

Collate data (RA)

Data collated

May-22

M1.4.3

Analysis of vascular lesion burden of data sample

Run analysis (RA)

Analysis completed

Jul-22

Deliverable 5: Image analysis of data sample for peri-vascular spaces

M1.5.1

Complete image analysis of data sample for peri-vascular spaces to provide inputs into work package 25b

Run analysis (RA)

Image analysis complete

May-22

Deliverable 6: Statistical analysis of peri-vascular spaces and vascular lesion burden data

M1.6.1

Complete the statistical analysis of data to provide inputs into work package 25c.

Analysis performed on DPUK data portal (RA)

Statistical analysis completed

May-23

Deliverable 7: Share resultant dataset using the DPUK Data Portal

M1.7.1

Share resultant dataset using the DPUK Data Portal

Create and share Data set with DPUK Data Portal (JW, RA)

Resultant dataset available on DPUK Data Portal

May-23

Deliverable 8: Findings from the analyses shared with the Vascular EM team

M1.8.1

Findings from the analyses shared with the Vascular EM team

Collate results and develop paper and presentation

Presentation of analysis findings to Vascular EM team

May-23

 

Objective 2: Define drug targets using Mendelian Randomisation (work package 25b)

Milestone

Description

How and who

Outcomes

Dates

Deliverable 9: Recruit Postdoctoral Research Assistant

M2.9.1

Recruit a Postdoctoral Research Assistant

Advertise and appoint to post (HM)

Research Assistant employed

Aug-21

Deliverable 10: Obtain data from UK Biobank

M2.10.1

Submit request and receive data from UK Biobank

Apply and receive data (HM, RA)

UK Biobank data downloaded

Nov-21

Deliverable 11: Identify and obtain appropriate additional data sources

M2.11.1

Identify appropriate additional data sources

Review datasets available (HM, RA)

Additional datasets identified

Oct-21

M2.11.2

Submit request and receive data from additional data sources

Apply and receive data (HM, RA)

Additional datasets downloaded

Nov-21

Deliverable 12: Incorporate data from work package 25a

M2.12.1

Incorporate data from work package 25a

Work package 25a shares data

Data incorporated into study

May-22

Deliverable 13: Complete initial Mendelian Randomisation studies looking into conventional risk factors and risk of MRI-defined small vessel disease

M2.13.1

Clean the downloaded data

Clean data (RA)

Data cleaned

Dec-21

M2.13.2

Collate the cleaned datasets

Collate data (RA)

Data collated

Jun-22

M2.13.3

Complete analysis of conventional risk factors

Run analysis (RA)

Analysis completed

Sep-22

Deliverable 14: Complete initial Mendelian Randomisation studies looking at novel risk factors and risk of MRI-defined small vessel disease

M2.14.1

Complete analysis of novel risk factors

Run analysis (RA)

Analysis completed

May-23

Deliverable 15: Statistical analysis of data from Mendelian Randomisation studies

M2.15.1

Complete the statistical analysis of data to provide inputs into work package 25c

Analysis performed on DPUK data portal (RA)

Statistical analysis completed

May-23

Deliverable 16: Share resulting dataset using the DPUK Data Portal

M2.16.1

Share resultant dataset using the DPUK Data Portal

Create and share the dataset with DPUK Data Portal (JW, RA)

Resultant dataset available on DPUK Data Portal

May-23

Deliverable 17: Findings from the analyses shared with the Vascular EM team

M2.17.1

Present findings to the Vascular EM team

Prepare findings and present to Vascular EM team (HM)

Presentation of analysis and results to Vascular EM team

Jun-23

 

Objective 3: Define drug targets using analysis of cardiovascular disease and drug history (work package 5c)

Milestone

Description

How and who

Outcome

Dates

Deliverable 18: Recruit a Clinical Research Fellow

M3.18.1

Recruit an Clinical Research Fellow

Advertise and appoint to post (TQ)

Research fellow employed

Apr-23

Deliverable 19: Obtain data from UK Biobank

M3.19.1

Submit request and receive data from UK Biobank

Apply and receive data (TQ, RF)

UK Biobank data downloaded

Jul-23

Deliverable 20: Identify and obtain appropriate additional data sources

M3.20.1

Identify appropriate additional data sources

Review datasets available (TQ, RF)

Additional datasets identified

Jun-23

M3.20.2

Submit request and receive data from additional data sources

Apply and receive data (TQ, RF)

Additional datasets received

Jul-23

Deliverable 21: Incorporate data from work packages 25a and 25b

M3.21.1

Incorporate data from work package 25a

Work package 25a shares data

Data incorporated into study

May-23

M3.21.2

Incorporate data from work package 25b

Work package 25b shares data

Data incorporated into study

May-23

Deliverable 22: Complete initial scoping analyses

M3.22.1

Clean the downloaded data

Clean data (RA)

Data cleaned

Nov-23

M3.22.2

Collate the cleaned datasets

Collate data (RA)

Data collated

Dec-23

M3.22.3

Complete analysis of conventional risk factors

Run analysis (RA)

Analysis completed

Jan-24

Deliverable 23: Choose drug targets using Delphi consensus

M3.23.1

Initial Delphi consensus questionnaire distributed

Construct and distribute questionnaire

Questionnaire responses received

Jan-24

M3.23.2

Subsequent Delphi consensus questionnaires distributed

Review initial questionnaire responses, construct and distribute subsequent questionnaires

Questionnaire responses received

Jan-24

M3.23.3

Results from Delphi consensus determined

Review all responses and determine consensus

Consensus determined and communicated

Jan-24

Deliverable 24: Complete analysis on DPUK Data Portal

M3.24.1

Complete analysis on DPUK Data Portal

Run analysis (RF)

Analysis completed

Jan-24

Deliverable 25: Publish a publication on the analyses conducted

M3.25.1

Write a paper for publication on the analyses conducted

Discuss and produce a publication on the scope of the work package and the results achieved, such as protocol document or a white paper (TQ, RF)

Paper written and submitted

Jan-24

M3.25.2

Paper published

Modifications as required (TQ, RF)

Paper published

Jan-25

Deliverable 26: Expert Consensus Panel formed

M3.26.1

Identify and invite members of the Expert Consensus Panel

Set up ECP (RF)

Panel meeting organised

Aug-23

M3.26.2

Feedback obtained from Expert Consensus Panel

Meet with ECP (RF)

Ideas and feedback from panel incorporated into project

Sep-23

Deliverable 27: Share resultant dataset using the DPUK Data Portal

M3.27.1

Share resultant dataset using the DPUK Data Portal

Create and share Data set with DPUK Data Portal (TQ, RF)

Resultant dataset available on DPUK Data Portal

Jan-25

Deliverable 28: Consensus meeting held including input from Industry partners and Clinical Trials work package

M3.28.1

Consensus meeting held including input from Industry partners and the Clinical Trials work package

Organise and host meeting

Meeting attended by Industry partners and Trial Delivery Framework leads

Oct-24

Deliverable 29: Findings from the analyses shared with the Vascular EM team

M3.29.1

Findings from the analyses shared with the Vascular EM team

Prepare and present findings to Vascular EM team (TQ)

Presentation of analyses and results to Vascular EM team

Jan-25

 

Objective 4: Collation of research across Vascular Health work packages

 

Milestone

Description

How and who

Outcomes

Dates

 

Deliverable 30: Vascular EM team to assess progress and focus subsequent directions

 

M4.30.1

Vascular EM team meet at least three times per year

Organise three per year (AH)

Meeting held in 2021 Q1

Mar-21

 

M4.30.2

Meeting held in 2021 Q2

Jun-21

 

M4.30.3

Meeting held in 2021 Q3

Sep-21

 

M4.30.4

Meeting held in 2022 Q1

Mar-22

 

M4.30.5

Meeting held in 2022 Q2

Jun-22

 

M4.30.6

Meeting held in 2022 Q3

Sep-22

 

M4.30.7

Meeting held in 2023 Q1

Mar-23

 

M4.30.8

Meeting held in 2023 Q2

Jun-23

 

M4.30.9

Meeting held in 2023 Q3

Sep-23

 

M4.30.10

Meeting held in 2024 Q1

Mar-24

 

M4.30.11

Meeting held in 2024 Q2

Jun-24

 

M4.30.12

Meeting held in 2024 Q3

Sep-24

 

Deliverable 31: Vascular EM team to discuss progress with Industry partners and other DPUK themes

 

M4.31.1

Vascular EM team to meet annually with industry partners and other DPUK themes

Organise 1 per year (AH)

Meeting held in 2021 Q4

Dec-21

 

M4.31.2

Meeting held in 2022 Q4

Dec-22

 

M4.31.3

Meeting held in 2023 Q4

Dec-23

 

M4.31.4

Meeting held in 2024 Q4

Dec-24

 

Deliverable 32: Annual review of milestones by Work Package leads

 

M4.32.1

Annual review of milestones by Work Package leads

Review with WP leads in years 2, 3 & 4 (AH)

Meeting held in 2022 Q4

Dec-22

 

M4.32.2

Meeting held in 2023 Q4

Dec-23

 

M4.32.3

Meeting held in 2024 Q4

Dec-24

 

Deliverable 33: Future studies developed and refined

 

M4.33.1

Planning for further Vascular EM studies

Look at funding and plans for the future

Planning performed

Dec-23

 

M4.33.2

Further refinement of planned Vascular EM studies

Review funding and refine plans

Further refinement performed

Dec-24

 

M4.33.3

Apply for funding for further Vascular EM studies

Specify studies and make funding applications

Funding applications submitted

Dec-24

 

Deliverable 34: DRI-DPUK Vascular theme interface maintained

 

M4.34.1

Vascular EM theme meet with DRI every 6 months

Organise 2 per year (AH)

Meeting held in 2021H1

Jun-21

 

M4.34.2

Meeting held in 2021H2

Dec-21

 

M4.34.3

Meeting held in 2022H1

Jun-22

 

M4.34.4

Meeting held in 2022H2

Dec-22

 

M4.34.5

Meeting held in 2023H1

Jun-23

 

M4.34.6

Meeting held in 2023H2

Dec-23

 

M4.34.7

Meeting held in 2024H1

Jun-24

 

M4.34.8

Meeting held in 2024H2

Dec-24

 

M4.34.9

Meeting held in 2025H1

Jun-25

 

M4.34.10

Meeting held in 2025H2

Dec-25

 

Objective 5: DPUK/MRC project reporting

Milestone

Description

How and who

Outcome

Dates

Deliverable 35: Produce quarterly reports by the required dates

M5.35.1

Provide Quarterly reports detailing project deliverables and outcomes.

Online quarterly form to be completed for DPUK for MRC meetings

Quarterly report submitted

Mar-21

M5.35.2

Quarterly report submitted

Jun-21

M5.35.3

Quarterly report submitted

Sep-21

M5.35.4

Quarterly report submitted

Mar-22

M5.35.5

Quarterly report submitted

Jun-22

M5.35.6

Quarterly report submitted

Sep-22

M5.35.7

Quarterly report submitted

Mar-23

M5.35.8

Quarterly report submitted

Jun-23

M5.35.9

Quarterly report submitted

Sep-23

M5.35.10

Quarterly report submitted

Mar-24

M5.35.11

Quarterly report submitted

Jun-24

M5.35.12

Quarterly report submitted

Sep-24

M5.35.13

Quarterly report submitted

Mar-25

M5.35.14

Quarterly report submitted

Jun-25

M5.35.15

Quarterly report submitted

Sep-25

Deliverable 36: Produce an annual report by the required dates

M5.36.1

Annual reports to oversee project status and updates of deliverables and outputs. Information to assess completion criteria as part of payment schedule.

Annual form to be completed for DPUK for MRC meetings.

Annual reports submitted to confirm milestone completion for next payment scheduled

Annual report submitted

Dec-21

M5.36.2

Annual report submitted

Dec-22

M5.36.3

Annual report submitted

Dec-23

M5.36.4

Annual report submitted

Dec-24

Deliverable 37: Provide annual financial reporting against the specified budget by the required dates

M5.37.1

Financial reports submitted at the end of each year. Information to assess completion criteria as part of payment schedule.

Yearly financial statement on spending

Financial report submitted

Dec-21

M5.37.2

Financial report submitted

Dec-22

M5.37.3

Financial report submitted

Dec-23

M5.37.4

Financial report submitted

Dec-24

M5.37.5

Financial report submitted

Dec-25

Deliverable 38: Produce a final work package report by the required date to summarise the work completed and the benefits achieved

M5.38.1

Final report submitted at end of project.

Lead to complete final report and send to DPUK /MRC for final payment to be made.

Final report submitted

Dec-25