Producing High Impact Research in the Field of Medicine

Cyrus Cooper OBE, DL, FMedSci

Professor of Rheumatology and Director, MRC Lifecourse Epidemiology Unit; and Vice-Dean, Faculty of Medicine; University of

Southampton; UK

Inside Government Forum – Future of UK REF; January 2017

High Impact Research in Medicine

• Faculty of Medicine, University of Southampton • Global burden of disease • The lifecourse approach: from theory to practice

– Musculoskeletal ageing – Childhood obesity

• Impact on Health Policy: Global, national & regional

MRC Lifecourse Epidemiology Unit, University of Southampton

University Hospital Southampton

Faculty of Medicine: Overarching Research Strategy

Translational Research

Converting knowledge into new treatments

and therapies

Interdisciplinary Research

Achieving step change in the generation of

new knowledge

Research Centre

Industry

Research Councils And Charities

Research Structure: Academic Units

• Cancer Sciences

• Clinical and Experimental Sciences

• Human Development and Health

• Primary Care and Population Science

• Medical Education

1,000 staff; £100m pa

Southampton Centre for Biomedical Research

• Clinical and biomedical research partnership with University Hospital Southampton NHS Foundation Trust

• Supported by £27M National Institute for Health Research funding

• NIHR/Wellcome Trust Clinical Research Facility

• NIHR Nutrition Biomedical Research Centre

• NIHR Respiratory Biomedical Research Unit

• NIHR/Cancer Research UK Experimental Cancer Medicine Centre

• MRC Lifecourse Epidemiology Unit

National Centres of Excellence in FoM, University of Southampton

6

MRC Unit/Centre CRUK Centre

NIHR BRU NIHR BRC CLAHRC

ARUK

REF 2014 University of Southampton: UoA1 (Clinical Medicine)

overall outputs impact environment

4* 25 16.9 61.3 12.5

3* 50 46.1 33.4 87.5

2* 21 31.1 5.3 0

1* 2 2.4 0 0

U 2 3.5 0 0

Category A fte = 143.39 Eligible staff Returned= 85%

• Large, inclusive submission with a high power index • 64% of our outputs are internationally excellent or world leading • Over 60% of our impact is World-leading and 94% 4*/3*. • We enjoy an excellent research environment (100% 4*/3*) • Improvement on RAE08 (128-143 fte; 10-17% 4*output; 0-12.5% 4*env)

HEI Power

UCL 1439.424

Imperial 1112.819

Oxford 823.722

Edinburgh 682.869

Cambridge 658.7315

Glasgow 567.68

Birmingham 499.016

QMUL 472.648

Newcastle 470.816

KCL 464.95

Liverpool 450

Manchester 434.4142

Southampton 422.1546

Nottingham 323.544

Leeds 292.02

Bristol 260.9505

ICR 230.0697

Leicester 218.463

QUB 211.968

Sheffield 200.803

Cardiff 191.7825

LSHTM 176.5296

Aberdeen 156.927

Dundee 150.48

St Georges 129.8

Warwick 98.6675

Exeter 77.42

Plymouth 45.82

StAndrews 44.64

UEA 42.624

0

200

400

600

800

1000

1200

1400

1600

0200400600800

1000120014001600

0 200 400 600

REF 2014: Research Power

Global Burden of Disease 2015 Most frequent causes of disability

GBD Collaborative Group Lancet 2015; 386: 2287-323 Newton J et al Lancet 2015; 386: 2257-74

Mis

sion

Mission

To develop preventive strategies against common, chronic musculoskeletal and metabolic disorders

Pro

gra

mm

es R

esea

rch

foc

us

Prog

ramm

es R

esearch focu

s

Nutrition and lifelong health

Development and body composition Health and work

Sarcopenia and frailty Bone and joint

MRC Lifecourse Epidemiology Unit 2015-2020

Child

Fetus & infant

Adult

Intervention Observation

Mechanisms

Developmental origins of adult disease

David Barker 1936-2013 Birth weight (pounds)

0

0

0

0

0

0

0

-5.5 -6.5 -7.5 -8.5 -9.5 >9.5

Osmond et alBMJ 1993

Lifecourse determinants of health and disease

ME

CH

AN

ISM

S

Developmental plastic responses Epigenetic processes

Childhood body composition and development

Infant feeding and illnesses

Infant body composition & development Weight gain and catch-up growth

Young women’s diet, body composition, physical activity, education and lifestyle before and during pregnancy

Childhood diet, physical activity, lifestyle and education

Vulnerability to chronic disease in later life

Work, lifestyle and health behaviours in adulthood

Retirement and ageing

Gluckman, Hanson, Cooper et al New Engl J Med 2008; 359: 61-73 Harvey N, Dennison E, Cooper C J Bone Miner Res 2014; 29: 1917-25

Chronic NCD risk

Plasticity

Life course

No intervention

Mother & infant

Earlier intervention improves functional capacity & responses to new challenges

Inadequate response to new challenges

Childhood

Adulthood

Early intervention

Late intervention

Late intervention impactful for vulnerable groups

Lifecourse strategy for disease prevention

Godfrey K et al Trends Endocrinol Metab 2010; 21: 199-205

Example 1 Musculoskeletal Ageing

Normal Bone Osteoporosis

Definition of Osteoporosis

A disorder characterised by low bone mass and microarchitectural deterioration of bone tissue leading to an increased risk of fracture

Impact of Osteoporosis-Related Fractures in Europe

Hip Spine Wrist Lifetime risk (%)

Women 14 11 13 Men 3 4 2

Cases/yr 615k 516m 560k

Hospitalisation (%) 100 2-5 5

Relative survival 0.83 0.82 1.00

All sites combined: n=3.5m; cost ~ 39 billion Euros

Hernlund E et al Arch Osteop 2013; 8(1-2): 136

Developmental origins of osteoporosis • LBW associated with reduced adult bone mass and strength

• Independent of known genetic determinants of BW and BMD

• Poor childhood growth predicts fracture

12,500 non-pregnant Southampton women aged 20-34 years interviewed about diet, body composition, physical activity, social

circumstances & lifestyle. Buccal and blood samples taken.

Subsequent pregnancies studied (n=3,160).

Ultrasound scans at 11, 19 & 34 weeks.

Interviews at 11 & 34 weeks

Maternal blood samplesPaternal buccal & blood

samplesMaternal grandparents’

buccal samples

Neonatal anthropometry.

Cord bloods

Children followed-up at 6, 12, 24 and 36 months;And at 4, 6, 8 & 10 years

Southampton Women’s Survey

Harvey N et al. J Clin Endocrinol Metab 2008; 93: 1676-81

Maternal vitamin D status and childhood bone mass

Maternal 25(OH) vitamin D (µg/L)

Javaid MK et al Lancet 2006;367:36-43

Princess Anne Hospital Cohort Study, Southampton; Age 9yrs

Distal femur splaying index = cross-sectional area (cm ²) ÷ length (cm)

p<0.001, r = -0.17,n = 391

<27.5 -50 -80 >800.04

0.06

0.08

0.10

Maternal 25-OH vitamin D (34 weeks gestation, nmol/L)

Spla

ying

inde

x

Mahon P et al J Bone Miner Res 2010; 25: 14-19 Ioannou C et al J Clin Endocrinol Metab 2012; 97: 2070-7 Yaqub M et al Fetal Diag Ther 2013; e-pub

Maternal vitamin D and automated intrauterine femoral measurement using 3D ultrasound

DNA methylation

Epigenetic mechanisms in vitamin D signalling

r = -0.175p = 0.007

2.45

2.5

2.55

2.6

2.65

2.7

WB

MH

- %

BM

C

to 53.0 to 66.0 to 82.0 > 82.0RXRA-3 Percentage of methylation

r = -0.199p = 0.002

2.45

2.5

2.55

2.6

2.65

2.7

WB

MH

- %

BM

C

to 45.0 to 56.0 to 73.0 > 73.0RXRA-2 Percentage of methylation

30 6

6

r=-0.18 p=0.007

r=-0.2 p=0.002

Harvey NC et al. J Bone Min Res 2014; 29: 600-7

BMC vBMD

Can we intervene during development?

Maternal vitamin D supplementation and childhood bone mass: the MAVIDOS

trial The MAVIDOS Trial Study Group

Cyrus Cooper1,2,3*, Nicholas C Harvey1,2,*, Nicholas J Bishop4, Stephen Kennedy5, Aris T Papageorghiou5, Robert Fraser6, Saurabh V Gandhi6, Stefania D’Angelo1, Sarah R Crozier1, Rebecca J Moon1, Nigel K

Arden3, Elaine M Dennison1, Keith M Godfrey1,2, Hazel M Inskip1, Inez Schoenmakers7, Ann Prentice7, Zulf Mughal8, Richard Eastell9, David Reid10, M Kassim Javaid3 and the MAVIDOS Study Group

1MRC Lifecourse Epidemiology Unit, (University of Southampton), Southampton General Hospital, Southampton, UK; 2NIHR Southampton Nutrition Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK; 3Oxford NIHR Musculoskeletal

Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford, UK; 4Academic Unit of Child Health, Sheffield Children’s Hospital, University of Sheffield, Sheffield, UK; 5Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK; 6Sheffield Hospitals NHS Trust (University of Sheffield), Sheffield, UK; 7MRC Human Nutrition Research, Elsie

Widdowson Laboratory, Cambridge, UK; 8Central Manchester University Hospitals, Manchester, UK; 9Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK; 10School of Medicine & Dentistry, Medical School, University of Aberdeen, Aberdeen, UK

Cooper C et al. Lancet Diabetes Endocrinol 2016; 4: 393-402.

Pregnancies at nuchal US scan

Booking (11/40)

Not eligible Randomisation

D3 1,000iu/d Placebo

Anthropometry, DXA

Anthropometry, DXA

Check 25D ALP, Ca, Albumin

Birth

4 years

14/40

Repeat 25D ALP, Ca, albumin, glucose 36/40

>100 nmol/l

25-100 nmol/l n=477

each arm

MAVIDOS Sub-studies:

•Bone turnover in mother/cord blood

•Maternal DXA

•Placental/cord epigenetic studies

•Maternal VDR genotyping

Vitamin D Supplementation in Pregnancy: The MAVIDOS Trial

Cooper C et al. Lancet Diabetes Endocrinol 2016; 4: 393-402.

Vitamin D supplementation increases offspring BMC in winter births

p=0.004

5060

70

Who

le b

ody

BM

C (

g)

Placebo 1000 IU/d

Winter

p=0.44

5060

70

Placebo 1000 IU/d

Spring

p=0.73

5060

70

Placebo 1000 IU/d

Summer

p=0.21

5060

70

Placebo 1000 IU/d

Autumn

Mean (95% CI) p interaction=0.04 p interaction = 0.04

Cooper C et al. Lancet Diabetes Endocrinol 2016; 4: 393-402.

Maternal vitamin D supplementation prevents decline in 25(OH)-vitamin D during pregnancy in winter and spring births

Placebo 1000 IU/day cholecalciferol

winter

spring

summer

autumn

2535

4555

6575

25(O

H)D

(nm

ol/l

)

14 34Gestation (weeks)

winter

spring

summer

autumn

2535

4555

6575

25(O

H)D

(nm

ol/l

)

14 34Gestation (weeks)

Cooper C et al. Lancet Diabetes Endocrinol 2016; 4: 393-402.

Conclusions of MAVIDOS trial

• Maternal antenatal vitamin D supplementation with 1000 IU cholecalciferol daily resulted in higher offspring bone mass in winter births

• Summer to winter decline in maternal vitamin D status abolished with supplementation

• 1000 IU cholecalciferol daily resulted in vitamin D repletion in over 80% of women

• These findings suggest that a stratified approach to vitamin D supplementation during pregnancy may be warranted

Example 2 Childhood Obesity

CHILDHOOD OBESITY

LOW/NO BREASTFEEDING,

UNHEALTHY COMPLEMENTARY

FOODS, UNHEALTHY

FAMILY BEHAVIOURS

MARKETING OF UNHEALTHY

FOODS AIMED AT CHILDREN

POOR SCHOOL FOOD, LOW PHYSICAL ACTIVITY,

SEDENTARY LIFESTYLE

LOW NUTRITION & HEALTH LITERACY

Origins of childhood obesity

0

10

20

30

40

50

60

None GCSED-G

GCSEA-C

A level HND Degree

Highest educational qualification

Educational attainment and dietary pattern in women of child-bearing age

Robinson S et al EJCN 2004; 58: 1174-78

% of women in lowest quarter of prudent diet score

Lack of money (food insecurity)

Food involvement

Expectations of outcome of eating

healthily

Social support for healthy eating

Why do women of lower educational attainment tend to have a poorer quality diet than women of higher educational attainment?

Quality of diet

General self-efficacy

Perceived control

Educational attainment

Lawrence WT et al Appetite 2011; 56: 46-52

Southampton Initiative for Health: A complex intervention to improve food choice among women of

child-bearing age

• Design – before and after non-randomised trial • Study population – women attending Sure Start Children’s

Centres, and their children

PRINCIPLE FINDING: Improvement in control and self-efficacy; more modest benefit on dietary pattern

Barker M et al J Hlth Psychol 2011; 16: 178-91 Baird J et al BMJ Open; 2014: 4: e005290

BEHAVIOUR CHANGE INTERVENTION: • 3 x 3 hour sessions over 5 weeks • 8 people per group with 2 facilitators • Session 1: Thinking about change • Session 2: Practising Healthy Conversations • Session 3: Embedding lasting change • Follow up: Ongoing contact with trained staff

Community nutrition environment

Organisational nutrition environment

Psychological factors

Perceived food accessibility

Environmental variables

Individual variables

Behavioural outcome

Food environment and dietary behaviour

Dietary behaviour

Consumer nutrition environment

Perceived food affordability

0.55**

-0.01

-0.02

-0.06

-0.15**

Standardised regression weights *<0.05, **<0.01

0.14*

-0.14*

Black C et al Int J Behav Nutr Phys Act 2014; 11:69

e" \ World Health

RKIOIW.omaFOA Europe

First announcement

WHO EuropeanMinisterial Conference

on the life-course approach in the context of Health 2020

The WHO European Ministerial Conference will bring together newevidence, from genetics to economics, on what governments cando to engender health throughout the life-course. The Conference

will equip policy-makers to promote a healthy start to lifeand to target the needs of people at critical ages.

Participants: Health min1sters. nat1onal delegations from Member States 1ntheWHO European Region, representatives from intergovernmental organizations, reg1onal

economic cooperation agenc1es and International nongovernmental organizations.

21 - 22 October 2015 Minsk, Belarus

I

, I _

( . \ World Health-Organization"""""'oma001 Europe

The life-course approachin the context of Health 2020:

From evidenceto policy and action

OFf:RE"J E-E-OTOf'..l

The MinskDeclarationThe Life-course Approachin the Context of Health 2020

(tfi l World Healtht ! Organization

- - ' ?

AEGIONALOFFicEFoR Europe

• Minimise childhood exposure to poverty and health inequalities • Recognise that education is a major social determinant of health • Promote quality preconceptional information/services/care, including women from disadvantaged backgrounds • Promote, support and protect breastfeeding • Support families to build parenting capacities • Develop or strengthen health-promoting structures and processes • Create safe and decent work environments and promote job security • Extend mother and child care to protect against stresses that may affect the next generation

The WHO Minsk Declaration Acting Early, Appropriately and Collectively

WHO European Ministerial Conference The Minsk Declaration (2015): Lifecourse approach in the context

of Health 2020 and Sustainable Development Goals

WHO 2016 Science & Evidence Working Group Chair: Mark Hanson

NICE Guidance Maternal vitamin D supplementation Prevention of childhood obesity

With thanks to all at the University of Southampton!