Million Women Study

Lead Research Organisation: University of Oxford
Department Name: Cancer Epidemiology Unit

Abstract

The Million Women Study is the largest study of women's health in the world. In 1996-2001, a quarter of UK females then aged 50-64 years (1.3 million women) joined the study. Study participants have provided details about their lifestyle and health and given signed consent for follow-up. Since then their health has been followed mainly through electronic linkage to routinely collected NHS records.

The aim of the study is to provide reliable information on potentially modifiable causes of common and serious illnesses, to help improve individual and public health. The study is jointly funded by Cancer Research UK, mostly for studies of cancer, and the Medical Research Council, mostly for studies of other conditions.

We have described links between smoking, alcohol, obesity, and use of hormone replacement therapy and women's risk of developing various diseases, recently reporting that the harms of smoking and the benefits of stopping were greater in women than previously thought.

This proposal is for research on dementia, osteoporosis, stroke and other severe disabling conditions that become increasingly common as women age. With this large study, detailed lifestyle information provided by women, and some 15 years follow-up through linkage to NHS medical records, we are uniquely placed to answer some major outstanding questions about what causes some of the serious conditions associated with ageing, and how they might be prevented.

We have already been able to link the study cohort to NHS records on death, cancer incidence, and hospital admissions. In the next 5 years we will enhance the linkage with newly-available information on medications prescribed and on conditions diagnosed in general practice.

Dementia is one of the most serious causes of disability as women age. There is surprisingly little good information about what people can do in middle-age to help prevent dementia occurring in later life. For example the effects of factors like smoking, alcohol, exercise and diet are still uncertain. Because dementia develops slowly over many years, and in the early stage can affect what people do, we need to study lifestyle factors over a long period before dementia is diagnosed. We will be able to follow large enough numbers of women for long enough to be able to provide reliable results, which other studies have not been able to do. With some 20,000 women in our study expected to develop dementia by 2017, we will also be able to study differences in risk factors for different types of dementia, such as Alzheimer's disease and vascular dementia.

Osteoporosis, where bones become weak and liable to fracture, is increasingly common as women age. Osteoporotic fractures of the hip and other bones are major causes of pain, disability and death. Bisphosphonate drugs, such as alendronate, are commonly prescribed to prevent fractures and their use is increasing rapidly. In recent years controversy about the balance between the benefits and risks of long-term use of these drugs has been ignited by reports of potentially serious side effects, which we plan to investigate.

We will also examine whether lifestyle factors in middle age, including diet and exercise, help prevent fractures occurring as women grow older.

This research will be made possible by combining the health information women have so generously given us with the excellent medical records available for the UK population through the NHS.

Technical Summary

In 1996-2001 we recruited a cohort of 1.3 million women, a quarter of the female UK population then aged 50-64 years. About 99% have been followed for more than 10 years for hospital admissions and deaths. Mean age is now 70 years and conditions associated with ageing, such as dementia and osteoporosis, are becoming increasingly common. We plan to focus on these emerging health problems, following the cohort for a further 5 years by electronic linkage to NHS records.

The increasing availability of electronic routinely collected NHS records has revolutionized questions that can be addressed in cohort studies. Only recently was it possible to obtain linked NHS records for cause-specific hospital admissions in England. Linkage to NHS primary care prescription and diagnostic data has just become available.

For women with a primary care or hospital record of dementia, we will confirm diagnoses and classify them by phenotype, where possible. We will then examine associations with postulated risk factors, taking care to avoid 'reverse causation bias' by focusing on the 15,000 women first diagnosed with dementia 10+ years after reporting risk factors.

Bisphosphonates are increasingly used for osteoporosis, but surprisingly little robust information exists about their safety. Recent reports of serious pathological lesions of the bone and other possible long-term side effects are stimulating debate about the balance between beneficial and adverse effects in users. Randomized trials have been too small, with too little follow-up, to evaluate such effects. About 10% of study participants have used bisphosphonates, permitting reliable assessment of their net effect, overall and by duration of use.

The uniqueness and timeliness of the research planned derives mainly from the size and maturity of the cohort, the wealth of prospectively collected personal data, and the virtually complete follow-up via electronic NHS records.

Planned Impact

The public will be the main beneficiaries of this research, both directly through better information about factors affecting their risk of developing common and serious diseases of middle age and of old age, and indirectly through our contribution to evidence upon which public health policy and guidelines are based.

Our research also contributes to better public understanding of science and engagement in research, particularly since most of our work is done as an integral part of the National Health Service.

Researchers in the UK and internationally, both in academic institutions and in the commercial sector, benefit from new knowledge on disease aetiology that we report and from the new methodologies we have pioneered. For example, we were among the first to use electronic methods for data-capture in epidemiological research, and are now initiating new research by harmonizing routinely collected NHS data from many sources, including hospital and primary care data collected in different databases in England and Scotland. We are regularly approached by other researchers about how to achieve such linkages.

The curation and availability of our data for future research will contribute to scientific research for decades to come.

Through excellence in research, we are helping to train future leaders in epidemiological and public health research. We hope to continue contributing to the research standing of UK universities and of the NHS and hence to funding and other economic benefits. The contribution that our study, and in particular the PI, has made to research and to public health has been recognised by the award of several major honours and prizes in recent years.

We hope that society as a whole will continue to benefit from our contribution to the improvement of public health, with the social and economic benefits this should bring.

Publications

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Armstrong M (2016) Relationship of Height to Site-Specific Fracture Risk in Postmenopausal Women in Journal of Bone and Mineral Research

 
Description advisory positions- please see Awards section.
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BHF Intermediate Transition Fellowship 2014-2016 [BC]
Amount £156,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 06/2016
 
Description Girdlers' New Zealand Health Research Council Fellowship [KB]
Amount $1 (NZD)
Organisation Health Research Council of New Zealand (HRC) 
Sector Public
Country New Zealand
Start 11/2014 
End 10/2016
 
Description Health of Vegetarians
Amount £402,643 (GBP)
Funding ID MR/M012190/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2015 
End 06/2020
 
Description Shiftwork and disease (HSE) 2009-2015
Amount £530,000 (GBP)
Organisation Health and Safety Executive (HSE) 
Sector Public
Country United Kingdom
Start 06/2009 
End 12/2015
 
Description Thrombosis UK Grant
Amount £5,000 (GBP)
Organisation Thrombosis UK 
Sector Charity/Non Profit
Country Unknown
Start 09/2015 
End 08/2016
 
Title Record linkage of large epidemiological data-bases 
Description We were the first group in England to successfully link a large database (The Million Women Study) with HES data. We have in 2014 obtained linkage to the primary care data in CPRD (and plan to link to equivalent datsets in Scotland) We have linked MWS data to that held by the NHS Cancer Screening Programmes. Our research staff have developed methods for reliable use of linked data in large epidemiological studies, including data dictionaries,derived variables and outcomes adjudication; we are working in collaboration with other UK cohorts. We have applied to link MWS data with that in UK Biobank. We have taken part in conferences on e-health research. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Many groups have consulted us about record linkage, and we regularly assist them in such work. We are working with UK biobank on validation studies on use of linked data eg for stroke and for neurodegenerative disease. Linkage with Cancer Screening will allow us to feed back information eg on characteristics of screened women which has the potential to improve service. 
 
Title Web-based questionnaires 
Description We have developed web-based questionnaires on diet and physical activity. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact UK Biobank has incorporated our web-questionnaires into their work. 
 
Title Oxford WebQ 
Description Online dietary questionnaire with automatic data coding by nutrient values. 
Type Of Material Database/Collection of data 
Year Produced 2012 
Provided To Others? Yes  
Impact The WebQ has been used by us and by UK Biobank to collect repeated measures of dietary intake for our large cohort studies. Data from the webQ will shortly be available for research use. Experiwence in using the webQ in UK Biobank has led to development of other online questionnaires, and so a new model of data collection in ongoing cohorts. 
 
Title RDCA 
Description Co-ordinated data access mechanism for active and legacy research studies in Nuffield Department of Population Health (NDPH). 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Developing policy for data access in NDPH 
 
Description BHFCRE 
Organisation University of Oxford
Department BHF Centre of Research Excellence
Country United Kingdom 
Sector Academic/University 
PI Contribution Cardiovascular research on Million Women Study and EPIC-Oxford cohorts contributes to the Population health component of the current round of funded research (2014-); CEU staff named as senior PIs for the BHFCRE; collaborative research projects with other Oxford groups within BHFCRE underway and planned.
Collaborator Contribution Collaboration on CVD research; opportunities for funding for specific projects and fellowships.
Impact Funding for feasibility study of genetic and environmental risk factors for aortic stenosis [Million Women Study].
Start Year 2011
 
Description CTSU 
Organisation Medical Research Council (MRC)
Department MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Unit
Country United Kingdom 
Sector Public 
PI Contribution Collaboration on a number of analyses of Million Women Study Data, particularly with respect to vascular disease epidemiology and statistical methods.
Collaborator Contribution Intellectual imput
Impact Several papers jointly written. Multidisciplinary - statistics and cardiovascular epidemiology
Start Year 2006
 
Description DementiasPlatformUK 
Organisation MRC Dementias Platform UK
Country United Kingdom 
Sector Public 
PI Contribution Contributing cohort with particular interest/expertise in outcomes adjudication for research using electronic health records.
Collaborator Contribution Collaboration on outcomes adjudication work -also includes UK Biobank and UK-wide neurodegenerative disease outcomes groups [including NOWG]
Impact None yet; platform launched October 2014
Start Year 2014
 
Description Economic costs of obesity 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiological expertise Data on obesity and use of primary and secondary care in the Million women Study cohort
Collaborator Contribution Expertise in health economics and health policy
Impact None yet
Start Year 2014
 
Description Investigation into child health using Taiwan healthcare data linkages 
Organisation Centers for Disease Control Taiwan
Country Taiwan, Province of China 
Sector Public 
PI Contribution Expertise
Collaborator Contribution Data, expertise
Impact Publications from collaboration: [Childhood cancer, type 1 diabetes and other immune diseases: healthcare visits in the year before diagnosis in Taiwan Yang TO, Huang WT, Chen MH, Huang KY, Chen PC. Arch Dis Child. Published Online First: 08 February 2017. doi: 10.1136/archdischild-2016-311762 Specific and non-specific clinical presentations in the year before the diagnosis of childhood leukaemia. Yang TO, Liu YL, Huang WT, Chen MH, Chen PC. Pediatr Blood Cancer. 2016 Aug;63(8):1387-93. doi: 10.1002/pbc.26029. PMID: 27128206 Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring. Yang TO, Huang WT, Chen MH, Chen PC. Epidemiol Infect. 2016 May;144(7):1512-9. doi: 10.1017/S0950268815002988. PMID: 26593706 Seasonal synchrony in incidences of common infectious diseases in early childhood among neighbouring regions. Yang TO, Huang WT, Chen MH, Chen PC. Int J Infect Dis. 2014 Oct 12; 28: 214-6. doi: 10.1016/j.ijid.2014.06.015. PMID: 25316330
Start Year 2014
 
Description Investigation into child health using Taiwan healthcare data linkages 
Organisation Chang Gung Memorial Hospital (CGMH)
Country Taiwan, Province of China 
Sector Hospitals 
PI Contribution Expertise
Collaborator Contribution Data, expertise
Impact Publications from collaboration: [Childhood cancer, type 1 diabetes and other immune diseases: healthcare visits in the year before diagnosis in Taiwan Yang TO, Huang WT, Chen MH, Huang KY, Chen PC. Arch Dis Child. Published Online First: 08 February 2017. doi: 10.1136/archdischild-2016-311762 Specific and non-specific clinical presentations in the year before the diagnosis of childhood leukaemia. Yang TO, Liu YL, Huang WT, Chen MH, Chen PC. Pediatr Blood Cancer. 2016 Aug;63(8):1387-93. doi: 10.1002/pbc.26029. PMID: 27128206 Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring. Yang TO, Huang WT, Chen MH, Chen PC. Epidemiol Infect. 2016 May;144(7):1512-9. doi: 10.1017/S0950268815002988. PMID: 26593706 Seasonal synchrony in incidences of common infectious diseases in early childhood among neighbouring regions. Yang TO, Huang WT, Chen MH, Chen PC. Int J Infect Dis. 2014 Oct 12; 28: 214-6. doi: 10.1016/j.ijid.2014.06.015. PMID: 25316330
Start Year 2014
 
Description Investigation into child health using Taiwan healthcare data linkages 
Organisation National Health Research Institutes (NHRI) Taiwan
Country Taiwan, Province of China 
Sector Charity/Non Profit 
PI Contribution Expertise
Collaborator Contribution Data, expertise
Impact Publications from collaboration: [Childhood cancer, type 1 diabetes and other immune diseases: healthcare visits in the year before diagnosis in Taiwan Yang TO, Huang WT, Chen MH, Huang KY, Chen PC. Arch Dis Child. Published Online First: 08 February 2017. doi: 10.1136/archdischild-2016-311762 Specific and non-specific clinical presentations in the year before the diagnosis of childhood leukaemia. Yang TO, Liu YL, Huang WT, Chen MH, Chen PC. Pediatr Blood Cancer. 2016 Aug;63(8):1387-93. doi: 10.1002/pbc.26029. PMID: 27128206 Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring. Yang TO, Huang WT, Chen MH, Chen PC. Epidemiol Infect. 2016 May;144(7):1512-9. doi: 10.1017/S0950268815002988. PMID: 26593706 Seasonal synchrony in incidences of common infectious diseases in early childhood among neighbouring regions. Yang TO, Huang WT, Chen MH, Chen PC. Int J Infect Dis. 2014 Oct 12; 28: 214-6. doi: 10.1016/j.ijid.2014.06.015. PMID: 25316330
Start Year 2014
 
Description Investigation into child health using Taiwan healthcare data linkages 
Organisation National Taiwan University
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution Expertise
Collaborator Contribution Data, expertise
Impact Publications from collaboration: [Childhood cancer, type 1 diabetes and other immune diseases: healthcare visits in the year before diagnosis in Taiwan Yang TO, Huang WT, Chen MH, Huang KY, Chen PC. Arch Dis Child. Published Online First: 08 February 2017. doi: 10.1136/archdischild-2016-311762 Specific and non-specific clinical presentations in the year before the diagnosis of childhood leukaemia. Yang TO, Liu YL, Huang WT, Chen MH, Chen PC. Pediatr Blood Cancer. 2016 Aug;63(8):1387-93. doi: 10.1002/pbc.26029. PMID: 27128206 Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring. Yang TO, Huang WT, Chen MH, Chen PC. Epidemiol Infect. 2016 May;144(7):1512-9. doi: 10.1017/S0950268815002988. PMID: 26593706 Seasonal synchrony in incidences of common infectious diseases in early childhood among neighbouring regions. Yang TO, Huang WT, Chen MH, Chen PC. Int J Infect Dis. 2014 Oct 12; 28: 214-6. doi: 10.1016/j.ijid.2014.06.015. PMID: 25316330
Start Year 2014
 
Description Life-long cancer risk among people who received transfusion in early life 
Organisation University of Sussex
Department Brighton and Sussex Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Data and expertise
Collaborator Contribution Data and expertise
Impact New collaboration, no impact yet
Start Year 2017
 
Description NSHD 
Organisation Medical Research Council (MRC)
Department National Survey of Health and Development (NSHD)
Country United Kingdom 
Sector Public 
PI Contribution Linkage of anthropometric and other data from MWS to data held by NSHD; analysis of comparison between measured and reported values
Collaborator Contribution Linkage of measured values from NSHD to MWS data Intellectual input for publication
Impact Publication (Cairns 2011)
Start Year 2010
 
Description Oxford WebQ 
Organisation UK Biobank
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collaborative development of online dietary questionnaire (the Oxford WebQ); in use by UKBiobank and MWS; MWS programmer led development.
Collaborator Contribution Programming and scientific input.
Impact Methods and validation publication: Liu et al 2011 Data collected in UK biobank for 200,000 particpants Within MWS for 20,000 participants
Start Year 2007
 
Description Physical Activity Profiling 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of 'physical activity profiles' scoring system to provide more meaningful information on disease risks in relation to physical activity.
Collaborator Contribution Development of 'physical activity profiles' scoring system to provide more meaningful information on disease risks in relation to physical activity.
Impact No publications yet
Start Year 2016
 
Description UKBiobank 
Organisation UK Biobank
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Membership of steering committee and International Scientific Advisory Board Contribution of MWS data to UK Biobank outcomes validation working group: stroke, neurodegenerative disease Development of online questionnaires on diet (the Oxford WebQ, developed in CEU and used by UKB) ,occupation, cognitive function.
Collaborator Contribution UK Biobank financial and staff support for outcomes validation and online questionnaires is relevant both to UKB and to our large epidemiological studies.
Impact The Oxford WebQ diet questionnaire [enquiries: krys.baker@ceu.ox.ac.uk].
Start Year 2011
 
Description genotyping 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution Blood samples for genotyping collected by Million Women Study. Data analysed by Million Women Study.
Collaborator Contribution DNA extraction and genotyping.
Impact 3 publications on joint effects of genetic and environmental risk factors for breast cancer (Travis et al, 2010; Reeves etal, 2010 and 2011).
Start Year 2006
 
Description genotyping 
Organisation National Genotyping Center (CNG)
Country France 
Sector Public 
PI Contribution Blood samples for genotyping collected by Million Women Study. Data analysed by Million Women Study.
Collaborator Contribution DNA extraction and genotyping.
Impact 3 publications on joint effects of genetic and environmental risk factors for breast cancer (Travis et al, 2010; Reeves etal, 2010 and 2011).
Start Year 2006
 
Description Epidemiology Lectures for the Introduction to Cancer Research Course 
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 Undergraduate students
Results and Impact June 2015/2016 Several researchers from the Unit gave an Epidemiology lecture for the 'Introduction to Cancer Research Course' run by the Department of Continuing Education, University of Oxford
Year(s) Of Engagement Activity 2015,2016
 
Description I'm a scientist 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Both researchers engaged with hundreds of children on a wide range of topics. The researcher who won the award received a prize which is being used to develop educational materials about science for schools.

Not measurable.
Year(s) Of Engagement Activity 2011,2012
 
Description Media: general 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Many of our findings are disseminated widely in the media and to policy makers, as our findings are often relevant to public health - eg the health consequences of alcohol consumption and of obesity in women; the effects of HRT; physical activity and vascular diseases

Our finging on HRT and alcohol have affected policy.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Prescribing policy: HRT 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact Our results have been summarized by the MHRA and have informed their prescribing guidelines both on use of HRT for menopause and on treatment of postmenopausal osteoporosis

Prescribing of HRT has declined and the incidence of breast cancer has declined in the UK and in other 'developed' countries where HRT was widely prescribed.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Schools outreach 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Research staff are active in organising activities and giving talks at schools to encourage an interest in epidemiology and science. Examples of school engagement activities include:
March 2017 Researchers ran a science fair for local secondary schools at Headington School, Oxford.
Nov/Dec 2016 Researchers visited year 5/6 students at Cutteslowe Primary School and Rose Hill Primary School to run an 'epidemiology in action' game on nutrition and cancer.
August 2016 UNIQ summer school; several researchers led sessions for the UNIQ Summer School, an Oxford University Scheme to attract and introduce sixth form students to careers in medical sciences and maths, with a particular focus on students with no family history of higher education or from schools who have not sent students to Oxford or Cambridge previously.
June 2016 Girl Guides Science Day. 50 girls (guides aged 10-14) visited the University for a Science Day. NDPH ran two 45 minute workshops, facilitated by researchers from the Cancer Epidemiology Unit .
March 2016 100 Sixth Form students visited as the Richard Doll Building as part of the Department of Oncology's annual schools day for National Science Week. Several researchers from the Cancer Epidemiology Unit ran stalls.
March 2016 Q and A session entitled 'I want to know about cancer...' at Glan Y Mor Secondary School, Camarthenshire.
August 2015 UNIQ summer school; several researchers led sessions for the UNIQ Summer School, an Oxford University Scheme to
attract and introduce sixth form students to careers in medical sciences and maths, with a particular focus on students with no family history of
higher education or from schools who have not sent students to Oxford or Cambridge previously.
March 2015 Schools day and open evening in the Richard Doll Building, Nuffield Department of Population and Health
Sept 2014 Oxford International Biomedical Centre, outreach talk to Oxfordshire year 12 and 13 students on nutrition and cancer
Year(s) Of Engagement Activity 2015,2016,2017
 
Description Science Fairs 
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 Research staff are active in having stalls with interactive games etc to help people understand our work and what it means at public Science Fairs eg:
Science in your world' Science Week 2013, Oxford: epidemiology game, discussions on cohort studies
Cancer Research UK Interactive Science Fair, Oxford: personalised medicine
Bright Sparks Brighton Science Festival 2014: obesity and cancer stall/activities
MRC Centenary Celebration Science Fair, London: epidemiology stall and activity
'Science Lates' event, Science Museum, London, September 2015
Oxford Science Festival, July 2016 WCRF Support Event, Worcester College, 2017
ScienceOxford 'Famelab', February 2017

Stalls and games provoke interest and engagement at the time. Further impact unknown.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description science open days 
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 Public/other audiences
Results and Impact Open days held at the Cancer Research UK Oxford Research Centre are attended by MWS staff; our posters present both cancer and some non-cancer work to local supporters and the general public .

Not measured.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
 
Description talks to participants 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact MWS researchers speak about the study at meetings of interested local groups (eg Women's Institute), including study participants.

2015/16 several researchers have spoken to the Nuffield Department of Population Health participant panel.

November 2016 one of researchers gave two lectures about the MWS to U3A meeting in Haddenham, Bucks

Not measured.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012