Statistics for Stratified Medicine and Analysis of Complex Phenotypes

Lead Research Organisation: University of Cambridge

Abstract

Many diseases and conditions, such as cancers, dementia and rheumatic disorders, are multi-factorial; exhibiting a range of biological manifestations that reflect the contribution of genetic and environmental factors. Even across individuals with rare diseases, which may result from single gene mutations, varying symptoms, health outcomes and treatment responses are seen. The complexity of diseases leads to many challenges ranging from understanding disease mechanisms and susceptibility to risk prediction and development and application of treatments. Stratified medicine, where "homogeneous" groups of people likely to respond similarly to treatment or have similar underlying disease mechanism or risk are sought based on biomarker information, is aimed at targeting therapies and optimal decision making for groups of patients who have shared biological characteristics. That genetic, molecular and imaging technologies have transformed biology has meant the need for those trained in analysing complex data, accounting for uncertainty and making evidence-based conclusions is paramount. Our programme will address statistical issues arising from using complex biological and clinical data for further understanding of diseases and to develop models aimed at risk prediction, stratified prevention, projection of disease course, treatment response, safety and the likelihood of adverse events and the tailoring of therapeutics to individuals.

Technical Summary

Stratified Medicine is a strategic priority for the MRC (and other organisations), and a substantial programme of investment by the MRC has begun and will continue for the coming years. The stratified medicine paradigm acknowledges the enormous biotechnological advances in generating and collecting detailed biological genotypic and phenotypic information across the various levels of organisation of the (human) biological system with the capacity to match the complexity of diseases and unmask patterns which can identify new and more subtle strata of disease. The unprecedented availability and progress of “omics” technologies for characterizing individual DNA mutations, metabolic profiles, protein expression and localisation, mRNA expression and epigenetic signatures in specific cell types, coupled with imaging and more traditional clinical, lifestyle and environmental data, have presented opportunities for further understanding of mechanisms, outcomes and molecular heterogeneity of diseases. This paves the way for individual-level models aimed at risk assessment and stratified prevention, projection of disease course, treatment response, safety and the likelihood of adverse events.

We will undertake a programme of statistical methodological research that encompasses risk stratification, prediction and validation, integrative and joint modelling of molecular and clinical data of various kinds and complexities (and their conversion into meaningful outputs that can inform health care decisions), mechanistic understanding and causality, treatment strategies and the design of innovative/purposeful clinical trials for biomarkers, rare diseases and dynamic treatment regimes. Both Bayesian and non-Bayesian methodology will be developed.

We are research partners in a number of MRC and other funded consortia in stratified medicine, and have close links with teams in North America, Europe and the UK. Our collaborations cover many diseases, medical conditions and areas. For example, we are involved in projects in rheumatology, dementia, rare diseases, HIV, antibiotic resistance and blood donation. Some of the goals of these projects are shared. We therefore envisage that methodology developed may be transferrable across diseases and medical areas, although tailoring may be required.

Publications

10 25 50
 
Description D&FP, Oxford- Lovestone
Amount £44,452 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2016 
End 05/2020
 
Description DPUK
Amount £243,698 (GBP)
Funding ID MR/L023784/2 
Organisation MRC Dementias Platform UK 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 06/2019
 
Description EPAD
Amount € 654,100 (EUR)
Funding ID 115736 
Organisation European Commission 
Department Innovative Medicines Initiative (IMI)
Sector Public
Country Belgium
Start 01/2015 
End 12/2019
 
Description GAUCHERITE
Amount £60,915 (GBP)
Organisation Medical Research Council (MRC) 
Department MRC Stratified Medicine
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 10/2017
 
Description HOD
Amount £122,542 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description NIHR TITRATE
Amount £129,168 (GBP)
Funding ID RP-PG-0610-10066 
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Public
Country United Kingdom
Start 10/2012 
End 12/2018
 
Description RA-MAP Consortium
Amount £61,882 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2011 
 
Description STEP-UP OA
Amount £103,946 (GBP)
Funding ID 22473 
Organisation Kennedy Memorial Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description VEhFIEFMQU4gVFVSSU5HIElOU1RJVFVURSBET0NUT1JBTCBTVFVERU5UU0hJUMKWIEFORFJFVyBN QU5ERVJTT04=
Amount £163,000 (GBP)
Organisation Alan Turing Institute 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 03/2022
 
Description Alzheimer's Societ grant with Patrick Chinnery, University of Cambridge 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-investigators and statistical lead
Collaborator Contribution Principal Investigator and expertise on rare variants
Impact Grant in early stage. No outputs yet. Multi-disciplinary - Biostatistics, Genetics, Neurodegenerative diseases
Start Year 2019
 
Description D&FP 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Statistical Lead
Collaborator Contribution Co-investigators on this MRC award
Impact None at present. Collaboration is multi-disciplinary; Psychiatrists, Clinicians, Statisticians, Bioinformaticians, Industry
Start Year 2016
 
Description DPUK 
Organisation MRC Dementias Platform UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Lead Work Package 14B - Statistics
Collaborator Contribution Funding
Impact Multi-disciplinary - academia, industry and clinicians Invited Talks: Statistical Challenges and Opportunities for Stratified Medicine. ITMAT Workshop on Data Science Challenges and Opportunities in Translational Medicine, Imperial College, London, UK 20th February 2017 and Combining and analysing multiple independent datasets. DPUK Annual Scientific Conference, London, UK 4th May 2017
Start Year 2016
 
Description EPAD 
Organisation European Commission
Department Innovative Medicines Initiative (IMI)
Country Belgium 
Sector Public 
PI Contribution Statistical Lead in the Disease Modelling of WP2
Collaborator Contribution Funding
Impact Multi-disciplinary: Clinical, Industrial, Statistical Talk: EPAD General Assembly, Barcelona, 2016 Publications: https://doi.org/10.1016/j.trci.2017.04.007
Start Year 2015
 
Description GAUCHERITE 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-applicant
Collaborator Contribution Principal Investigators
Impact None yet
Start Year 2013
 
Description GAUCHERITE 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-applicant
Collaborator Contribution Principal Investigators
Impact None yet
Start Year 2013
 
Description MASTERPLANS 
Organisation University of Manchester
Department Faculty of Medical and Human Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-applicants who are providing the statistical expertise to this MRC stratified medicine initiative in systemic lupus erythematosus
Collaborator Contribution Principal Investigator
Impact Collaboration is multi-disciplinary bringing together industry and academic experts, covering basic, clinical, therapeutic development and biostatistical research, in this lupus stratified medicine consortium
Start Year 2015
 
Description NIHR TITRATE 
Organisation King's College Hospital Charity
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Co-applicant
Collaborator Contribution Principal Investigator on NIHR Programme Grant
Impact Publications: https://doi.org/10.1186/s13063-017-2330-8
Start Year 2012
 
Description RA-MAP Consortium 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-applicant
Collaborator Contribution Principal Investigators in the MRC/ABPI Immunology and Inflammation Initiative for Inflammatory Joint Disease
Impact Talks: Inventory of Trials Workshop, Manchester 2014; PSI Conference, London 2015; TACERA Meeting, MEDIMMUNE, Cambridge 2015; RA-MAP Premier Meeting, London 2016; PSI Immunology Meeting, ROCHE, Welwyn Gardens City 2016; MATURA Scientific Meeting, QMUL, London 2017 Publications: doi:10.1038/nrrheum.2017.200
Start Year 2011
 
Description RA-MAP Consortium 
Organisation Newcastle University
Department Institute of Cellular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-applicant
Collaborator Contribution Principal Investigators in the MRC/ABPI Immunology and Inflammation Initiative for Inflammatory Joint Disease
Impact Talks: Inventory of Trials Workshop, Manchester 2014; PSI Conference, London 2015; TACERA Meeting, MEDIMMUNE, Cambridge 2015; RA-MAP Premier Meeting, London 2016; PSI Immunology Meeting, ROCHE, Welwyn Gardens City 2016; MATURA Scientific Meeting, QMUL, London 2017 Publications: doi:10.1038/nrrheum.2017.200
Start Year 2011
 
Description ADVANCED MUSCULOSKELETAL SUMMER SCHOOL 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Taught on the Advanced Musculoskeletal Summer School in Manchester on the 5th July 2016. Delivered the Survival Analysis and Multi-state Models module. This was attended by clinicians, allied health professionals, and researchers working in musculoskeletal research
Year(s) Of Engagement Activity 2016
 
Description Armitage Lectures 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual workshop and lecture created and hosted by the MRC Biostatistics Unit, to honour the immense contributions of Professor Peter Armitage who was at the unit from 1947 to 1961, and whose work is recognised throughout the world as achieving a successful balance between methodological rigour and applied commonsense, to which all statisticians aspire. An eminent medical statistician visits for a week and works with members of the unit. The highlight is the Armitage Lecture, where more than 100 delegates attend. This event raises the unit research profile and creates new collaborations.

Brian Tom was the scientific lead for the 2016 event - identifying a suitable Armitage speaker, and providing scientific oversight across all matters relating to the event.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
URL https://www.mrc-bsu.cam.ac.uk/news-and-events/armitage-lectureships-and-workshops/
 
Description Armitage Workshop 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual BSU Armitage Workshop - scientific development and organisation from Dr Brian Tom.
Workshop attracted international keynote speaker from Princeton University and 110+ delegates from across the UK from academia and industry.
Year(s) Of Engagement Activity 2018
 
Description Armitage Workshop 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Annual BSU Armitage Workshop - scientific development and organisation from Dr Brian Tom. Workshop attracted international keynote speaker from Harvard University and 100+ delegates from across the UK from academia and industry.
Year(s) Of Engagement Activity 2019
 
Description BSU Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Unit held open day as part of MRC Festival of Medical Research.

The aim of the open day was to welcome secondary school students and members of the general public to come to the unit, find out about the research the unit does, and to take part in activities that illustrate BSU research, with the overall theme being 'Fun with statistics'. An open day of this format was a first for the unit and overall it was a very successful event. There were 40 attendees over a 4 hour event. All attendees pre-booked and were split into 4 groups for a 1 hour session comprising of an introduction, participation in hands-on activities, and a brief careers talk. The small groups and length of session allowed for quality engagement between the scientists and the audience.

Feedback from the attendees was very positive, and the wider MRC Festival activities that took place in Cambridge demonstrated the benefits in delivering these types of events.
Year(s) Of Engagement Activity 2016
URL http://www.mrc-bsu.cam.ac.uk/bsu-open-day-2016-why-are-statistics-important/
 
Description Berkeley Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk at a Global Alliance Meeting in Precision Medicine held at University of California Berkeley. Attendees were from the National University of Singapore, University of Cambridge, University of California San Francisco and University of California Berkeley
Year(s) Of Engagement Activity 2016
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Each year BSU participate in Cambridge Science Festival - members of the general public explore and discuss issues of scientific interest and concern, through a series of different events. The festival also aims to raise aspirations by encouraging young people to consider a career in science, technology, engineering or mathematics.

BSU take part over two full days - 'Science Saturday' and the 'Cambridge Biomedical Campus' day. The unit presents a stand with 4 - 5 interactive activities that each communicate a basic statistical method or idea, representing one of the four research themes in the unit. Each year a new activity is developed and delivered requiring scientific input from staff and students across the unit. Over the two days, BSU engage with approximately 500 adults and children who visit the festival.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016,2017
 
Description Cambridge Science Festival 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Stand at Cambridge Science Festival 2019, presenting two interactive hands-on activities developed by researchers across the BSU; one explaining probability and risk, and the other on precision medicine. Reaching out to 500+ audience members over 1 day.
Year(s) Of Engagement Activity 2019
 
Description EPAD General Assembly Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Update Talk on the Disease Modelling work done in WP2.
Year(s) Of Engagement Activity 2016
 
Description LMS Prospects in Mathematics Meeting 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Brian Tom was an Invited Speaker at the London Mathematical Society Prospects in Maths Meeting in Lancaster to promote postgraduate research in Mathematics across the UK
Year(s) Of Engagement Activity 2019
URL https://www.lancaster.ac.uk/maths/pim2019/
 
Description MATURA Scientific Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave an overview of the RA-MAP Biostatistics Experience.
Year(s) Of Engagement Activity 2017
 
Description Media enquiry - BBC 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Article in BBC News (http://www.bbc.co.uk/news/health-37131836) and feature on BBC Radio 4 about new research to help spot early signs of Alzheimer's - based on published research co-authored by Brian Tom, Programme Leader Track http://www.mrc.ac.uk/news/browse/world-s-most-in-depth-study-to-detect-early-signs-of-alzheimer-s-disease/
Year(s) Of Engagement Activity 2016
 
Description Patient and Public Involvement and Engagement Activity - Talk to Advisory Committee 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Yuejia Xu presented her work to the Advisory Committee of 8 members of public involved with the Blood and Transplant Research Unit
Year(s) Of Engagement Activity 2019
 
Description Peter Holmes Prize 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Simon White awarded Peter Holmes prize for article in Teaching Statistics entitled 'Investigating populations via penguins and their poo!'. In honour of the journal's founding Editor, the Peter Holmes Prize is awarded to the best classroom idea published in Teaching Statistics in a given year.

Simon's article, written with a collaborator, is about demonstrating to 1118 year-olds how population modelling using sampling works. It describes an activity that uses toy penguins and poo emojis to d
Year(s) Of Engagement Activity 2019
URL https://onlinelibrary.wiley.com/doi/10.1111/test.12217
 
Description School visit by group of secondary school students from Switzerland 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Visit to Unit by group of 20 secondary school students from Switzerland - talk by Shaun Seaman on the work carried out by the Unit and potential career paths in statistical research,
Year(s) Of Engagement Activity 2018
 
Description Toronto PsA Meeting Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk at the Scientific Meeting of the University of Toronto Psoriatic Arthritis Clinic. The attendees were clinicians, researchers, patient group members, funders and Industry.
Year(s) Of Engagement Activity 2017
 
Description Toronto PsA Meeting Talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave a talk at the Scientific Meeting of the University of Toronto Psoriatic Arthritis Clinic. The attendees were clinicians, researchers, patient group members, funders and Industry.
Year(s) Of Engagement Activity 2016
 
Description Toronto Psoriatic Arthritis Meeting 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Brian Tom gave a talk at Scientific Meeting of University of Toronto Psoriatic Arthritis Clinic. The attendees were clinicians, researchers, patient group members, funders and industry
Year(s) Of Engagement Activity 2019