DISseminating knowledge of COvid-19, Vitamin D & Ethnic Risk: DISCOVER

Codesigned bench-to-bedside-to-behavioural change partnership project, methodically identifying/verifying/validating/disseminating (including this/others’ solutions) ethnicity-specific microRNA profiles and vitamin D influences on COVID-19 risk.

Dr Fraser Birrell
Director of Science & Research, British Society of Lifestyle Medicine 
Engagement Lead, MRC-Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing- CIMA
Editor-in-Chief, Lifestyle Medicine
Principal Fellow, Higher Education Academy

The problem is inequality: stark data proves Black Lives Matter->139m COVID-19 cases/3m deaths as of 15/4/21; poorer, older, unhealthy and certain ethnic groups experiencing 2-3x worse mortality per risk factor, exacerbated by poor healthcare engagement. One hypothesis: low vitamin D levels (D3) in high-risk ethnic groups impair immune response to SARS-CoV-2 infection, both with initial infection and/or later hyperinflammation. Few studies have examined the association between low D3 and infection rate, whether low D3 is a cause/consequence of infection; and whether these explain ethnic differences. UK-Biobank cohort analysis found D3 measured 10-14 years previously and COVID-19 incidence/mortality were associated, but limited ethnicity subgroup analysis was performed and significance was lost after, arguably, statistical over-adjustment. Another evidence gap is D3 trajectory during ongoing severe COVID-19 infection and ethnic variations. One open-label pilot trial showed that D3 supplementation was highly protective against ICU admission (2%vs.50%, p<0.001), but needs replication. 

Further research in these areas is vital, elucidating: 

• Factors/biomarkers predicting more severe pandemic diseases, particularly identifying ethnic groups at highest risk of severe disease/death 

• Potential of D3 supplementation to prevent severe disease with hyperinflammation 

• More granular understanding of the molecular mechanisms of onset, progression and recovery across high-risk ethnic groups

Our solution helps marginalised/high-risk ethnic groups impacted disproportionately by COVID-19 globally (including black, brown, indigenous, and people of colour; BBIPOC). 

We seek equitable outcomes: 

1) Identifying ethnic risks, informing D3 supplementation strategies and better understanding societal factors’ biochemical/metabolic health implications 

2) Identifying disease outcome predictors by ethnicity 

3) Explaining pandemic disease mechanisms 

4) Unlocking new treatment avenues 

5) Addressing inequality with empowering, codesigned healthcare choices 

We recognise strength in diversity; our team is multidisciplinary/multi-ethnic. Our patient representatives from Black African/Bangladeshi communities, amongst others, strongly support this project. One emerging key theme is skin tone, dramatically affecting D3 production in sun-exposed skin. Despite each having their own experience and associated societal risk factors, BBIPOC groups feel skin tone is used to label/profile them in healthcare research, driving further discrimination. As race is socially-constructed rather than genetic, racialised health-risk social factors will likely have unique epigenetic signatures, making transcriptomic analyses a crucial tool for understanding. Inclusion in high-quality research is a vital step in taking back ownership of colour itself. If funded, our extensive patient and public panel will work on integrating skin tone measurement (e.g. skin tone validated against standardised colour charts) and appropriate ethnic representation in UK Biobank/other cohorts.

Solution’s public good includes: 
- Addressing health inequities related to ethnicity/race/poverty 
- Development of clinical biomarker tests/promising treatments for novel targets made available on a non-profit basis to developing countries 
- Validated, generalisable microRNA/sRNA profiles of ethnic subsets from CORONAVIT, UK-Biobank cohort & ISARIC 4C for future diagnostic and therapeutic developments and research community use 
- Value of further microRNA/sRNA profiling of UK-Biobank cohort 
- Vitamin D analysis of whole UK-Biobank COVID substudy & ISARIC 4C cohorts for future research community use 
- Continuing to share VGC models globally to deliver better care for lower cost to more people with high patient and staff satisfaction 
- Share findings from all funded Trinity Challenge solutions through direct VGC engagement 
- Peer-reviewed publications on: 
1) Validation of capillary vitamin D 
2) MicroRNA biomarkers of COVID-19 by ethnicity 
3) MicroRNA and vitamin D prediction of COVID-19 outcome 
4) Changes in microRNA & vitamin D profiles with COVID-19 
5) BAME precision medicine insights from epigenetics 

These will deliver improved information for health policymakers (including WHO & NICE e.g. NG10179: https://www.nice.org.uk/guidance/indevelopment/gid-ng10179), healthcare providers, industry, public and patients to guide policy, practice and behaviours: informing decisions on vitamin D testing/replacement in populations & clinical practice.

Tangible impact: 
- for researchers/policy makers, outlined above 
- for populations, delivered by generalisable results from three cohorts 
- for individuals, comes from knowledge/support/access to VGC care 

Impact will come from sharing results quickly and effectively through novel channels (VGCs/patient representative networks/award-winner’s smartphone films) plus established ones (open-access publications, websites, social media). Inequality will be directly addressed by putting new ways of understanding differences (in chronic and infectious disease outcome) into the public domain and solutions (routine/targeted D3 supplementation, lifestyle interventions, access to new tests and treatments). 

Activities are done by the right people in the right organisation at the right time, leading directly to timely results, sharing and behaviour change (for patients and clinicians). 

Evidence for links: 
- Strong: exponential British Society of Lifestyle Medicine growth to >1500 members since 2016 
- Deep: https://bslm.org.uk 8746 unique users (mean 6-min stay), 36,000 page-views 1st 10 weeks 
- Global: 2854 from 60 countries registered for first ten VGC webinars: mainly clinicians, but also patients/researchers; another 4071 views on https://bslm.org.uk/vgc/. VGC typically have 12-15 patients/session/clinician, so patient-reach orders of magnitude greater 
- Holistic: VGCs deliver care, engage, empower and create time/space to share all funded Trinity Challenge solutions

We already know that group consultations empower patients, enabling peer-supported personal behaviour change. The progression to VGCs is even more important, allowing safe delivery of care even under pandemic conditions. Scaling this model of care is key, training clinicians and facilitators using a train-the-trainer model equipping nations to prepare their own healthcare systems for recovery and future pandemics. The gains are greatest for populations with the least resources and the highest risk groups, sustainably addressing inequality. This will happen concurrently with the translational epidemiology, enabling maximum impact at every time point: 

Scaling Over One Year 
- D3, microRNA and sRNA analyses performed, enabling sharing of initial results 
- Ensuring 1500 teams trained to deliver regular VGCs including personalised D3 goals 
- Goal: training 1000 more teams, leading to impact for >1 million patients 
- VGC training/patient representatives embedded in 10 countries 
- 80 countries engaged 

Scaling over three years 
- Top microRNA/sRNA hits verified and validation across the other cohorts, enabling final results to be shared 
- Ensuring the 2500 teams trained deliver regular VGCs 
- Goal: training 10,000 more teams leading to impact for >10 million patients 
- VGC training/patient representatives embedded in 50 countries 
- 100 countries engaged

See attached Gantt chart. 

Monitoring achievement of milestones/publications: 
- Vitamin D analysis of whole UK Biobank COVID substudy & ISARIC 4C cohorts 
- MicroRNA/sRNA profiles of ethnic subsets from CORONAVIT, UK-Biobank cohort & ISARIC 4C 
- Verification of biomarkers 
- Cross-validation 
- Development of clinical biomarker tests 
- Novel targets - Novel treatments 

Evaluating VGC spread impact on care systematically as the forgotten group consultations pioneer, Pratt (https://jamanetwork.com/journals/jama/article-abstract/443820) would do today by: 
- number of countries adopting (target:50) 
- number of clinicians/teams trained (target:10,000) & patients (target:10m) 
- assessment against the quadruple aim: better care for lower cost to more people with high satisfaction for patients and staff 
- better care: proportion achieving treatment target (e.g. diabetes HbA1c 48mM or personal target if no condition-specific target) 
- lower cost: cost/QALY derived from longitudinal EuroQol/EQ-5D data 
- number of patients per group & per unit clinician time 
- satisfaction using validated tools 

Evaluating impact of research outputs on engagement by: 
- smartphone films: views, likes of and awards 
- website analytics: unique users, mean duration of viewing, page-views 
- number of Trinity Challenge core outputs allocated for sharing through global VGC network 
- specific feedback on core outputs shared through VGCs

The main barriers for the research element of our solution are financial and technical- namely full approval for access to ISARIC 4C/UK-Biobank samples, which requires guaranteed funding. These will be overcome by securing funding through Trinity Challenge. 

Barriers for VGC adoption include training gaps and infrastructure challenges plus language, cultural and financial (especially reimbursement, a particular issue for insurer-based health economies). 

Education is addressed by Sir Jules Thorn Trust funding establishing a virtual training and evaluation hub, supporting development of website/app training resources which are available free-to-use, as are the VGC webinar programme. We have included translation in our solution: that and the cultural issues are addressed by our train-the-trainer model, which embeds codesign and context-specific VGCs (e.g. Aboriginal ‘Yarn Ups’). Infrastructure is important, including digital exclusion (addressed by e.g. UCSF Psychiatry’s philanthropic model) and platform choice, informed by country and organisational guidelines/priorities. Having successfully secured reimbursement approval and coding in the challenging USA environment, that innovation and sharing proven strategies makes the barrier lower elsewhere, as does growing evidence of cost-effectiveness. 

Minimum resource for implementing VGCs is a clinician & facilitator with support for implementation. Once patients are consulted/engaged they become huge advocates of this empowering model of care.

American College of Lifestyle Medicine (LM) 

Australasian Society LM

British Society LM 

Group Consultations Ltd 

Korean College LM 

The Society of Lifestyle Medicine of Nigeria 

World Lifestyle Medicine Council/Lifestyle Medicine Global Alliance 

Brighton/Sussex Medical School 

Newcastle University 

Queen Mary University, London 

Swansea, Kent, Chester & Washington Universities

HTG Molecular

Roche 

We are applying because of belief in partnership and that global solutions need global collaboration. UKRI has lacked the vision to fund our previous proposals to spread these models globally, including proposals as an engagement modality (UKRI-NSFC joint call) and for spread within exemplar low/low-middle/middle income nations (Tanzania, Sri Lanka & Malaysia) for the Global Alliance for Chronic Disease while still under the MRC, believing them over-ambitious, despite meeting the vision for UK spread. Since those rejections, VGCs have made training and delivery of group consultations cheaper, there is proof-of-concept for international training (Korea/Nigeria) and pandemic-deferred chronic care delivery makes the case even more compelling. 

UKRI is a victim of UK’s international aid budget cut from 0.7-0.5% GDP, reducing international development project budget from £245m to £125m. Therefore, the chances of conventional funders making such a leap of faith in a project wrongly perceived high-risk and overambitious is vanishingly small. 

In contrast, the Trinity Challenge does not just bring resources, it brings real partnership opportunities and both a shared level of ambition and credibility from partners with global reach and excellence in their respective fields. Given the alignment with our values and strategies, the surprising thing would be not applying.

We want to partner with likeminded researchers, healthcare providers & insurers, technology companies and any organisation which can provide fresh ideas, triangulate our perspective and/or help deliver our vision. 

As well as all the current and future Lifestyle Medicine Global Alliance (LMGA)/World Lifestyle Medicine Council (WLMC) members (this organisation has transitioned to WLMC, chaired by Rob Lawson, but most websites still refer to LMGA), the (non-exclusive, but based on known interest/expertise) list of potential partners includes: 

Partners in Innovation
University of Cambridge, Imperial College, National University of Singapore, Northeastern University, Hong Kong University, London School of Economics, Institute of Health Metrics and Evaluation, Global Virome Project, Joep Lange Institute, Fundação Oswaldo Cruz 

Exploring Healthy Ageing
Clinton Health Access Initiative, Bay Area Global Health Alliance, Optum, Swiss Re, Aviva, Legal & General, Discovery 

Leveraging Data Solutions for Geo-spatial VGC Spread & Impact
Google, Microsoft, Facebook, Tencent, Bluedot, GSK, Cuebiq, Doctor Evidence, Infosys, Zenisys, Enterprise 

Novel microRNA/sRNA Biomarker Tests/Therapeutics
Qiagen, Alnylam Pharmaceuticals, Ionis Pharmaceuticals, miRNA Therapeutics, Massachusetts Institute of Technology, Regulus Therapeutics, Viridian Therapeutics, Santaris Pharma, Regeneron, Pfizer, Abbvie, Lilly 

Sustainably Addressing Structural Inequality
Bill & Melinda Gates Foundation, Patrick J McGovern Foundation, Palantir, Brunswick Group, McKinsey & Company, Internews, Metia