The answers are in the numbers. By conducting an analysis on a scale never attempted before, Professor John Danesh and his team at the University of Cambridge’s Cardiovascular Epidemiology Unit (CEU) in the Department of Public Health and Primary Care are gaining new insights into the causes of, and potential interventions into, CVD.

Bigger is better

Since the late 1940s, when the Framingham Heart Study in the USA first undertook the ambitious task of following the development of CVD in a large group of individuals over a long period of time (originally around 5,000 healthy men and women), many longitudinal population studies into CVD have been conducted across the world. Each strives to understand, predict and prevent a global epidemic that currently causes 17 million deaths per year.

Many of these early studies identified the major CVD risk factors that are now so familiar to us – high blood pressure, high blood cholesterol, smoking, obesity, diabetes and physical inactivity. But a significant number of people who succumb to cardiovascular events do not display any of these warning signs.  In recent years, many new or emerging risk factors have been proposed, among them mediators and products of the inflammatory system.

Over a decade ago, Danesh realised that by pulling together the large number of existing population studies into a dataset of unprecedented size and potential, he and his team could use the power of scale to understand the risk factors for CVD as never before. In 2003 he established the Emerging Risk Factors Collaboration (ERFC), an international collaboration that collates the work of 130 epidemiological studies from more than 20 countries, creating a primary dataset that comprises information collected from around 2.5 million healthy volunteers.

“With this central database we can combine exceptional power and exceptional detail,” said Danesh, Director of the Unit and Head of the University’s Department of Public Health and Primary Care. “The ERFC has information on many risk factors, both known and suspected, for CVD, and also information on the resurveys of these risk factors at different time intervals in large subsets of the people. Up to 100,000 of the 2.5 million individuals involved developed a new onset of heart attack or stroke after their entry into the study, making the collaboration extremely valuable for evaluating potential cardiovascular risk factors.”

The enterprise has not been without its challenges. Emanuele Di Angelantonio, a University Lecturer in Medical Screening and part of the team using the dataset to reanalyse and assess novel risk factors for heart disease, explained: “There are many technical issues involved in working with such a massive dataset from so many sources. Different studies define risk factors in slightly different ways, and we had to come up with clever algorithms to standardise these so we can address the questions in the correct way. Another challenge was the statistical analysis. When science reaches a certain scale, it merges with all sorts of other considerations. We had to come up with whole new statistical methodologies to support the research programme.”

Improving clinical practice

By conducting detailed re-analyses of data collected worldwide, the ERFC is starting to provide reliable answers to long-standing clinical controversies surrounding the assessment of people’s risk of heart disease, helping to define exactly what it is useful to measure. Important lipid and inflammatory biomarker findings are already emerging that have implications for clinical practice.

“If you’ve ever had your blood cholesterol measured, the convention is that you fast overnight first because that was thought to provide the best measurement for an optimal prediction of heart attack risk,” said Danesh. “In fact, a report from this collaboration suggests that non-fasted, or random samples are at least as good, potentially even better, than fasted samples. It’s also been the convention to measure levels of a type of blood fat called triglyceride, but our work suggests that once you have the cholesterol information, the triglyceride information is not at all useful.”

The work has also identified a new causative risk factor, a novel blood fat called lipoprotein-a, the relevance of which to the risk of heart attack had previously been uncertain for a long time. “Because the contribution of lipoprotein-a to the risk of heart attack is only about a quarter of the strength of the contribution of bad cholesterol, we required a much larger study to identify and confirm its effect than we would for really strong risk factors,” explained Danesh. “This positive confirmation has only been possible because of the power provided by the unprecedentedly large dataset of the ERFC.”

Such evidence has been cited by the 2011 guidelines of the European Atherosclerosis Society consensus panel for therapeutic targeting of patients with elevated triglycerides and/or low levels of good cholesterol, and by the 2010 guidelines of the European Atherosclerosis Society recommending lipoprotein-a for use in cardiovascular disease risk assessment. It has also informed phase III clinical trials of a drug called darapladib, by GlaxoSmithKline, for the treatment of atherosclerosis, and encouraged the American College of Cardiology Foundation/American Heart Association Task Force to recommend assessment of mass concentration of lipoprotein-associated phospholipase for targeted cardiovascular disease risk assessment in their 2010 guidelines.

Adding genetics to inform medical interventions

The ERFC provides useful data on the correlations between levels of biomarkers in the blood and their association with the risk of heart disease. But there is a difference between biomarker molecules that are associated with heart disease and those that actually contribute to it.

Dr Adam Butterworth, a University Lecturer in the CEU, has been trying to identify the causal biomarkers by finding related genetic variants that are associated with heart disease. “For example, the idea of a link between heart disease and inflammation has been around for a long time, but it has proven difficult to identify specific biomarkers and genes to explain that link,” he said.

A new collaboration, taking the same large-scale approach as the ERFC, has used human genetics to show that a functional allele (a variant of a gene) in an inflammation-related gene is convincingly associated with heart disease. “The IL6R Genetics Consortium is a collaboration of 46 genetic studies that was created to investigate the effects of a specific genetic variant in the interleukin-6 receptor (IL6R) gene on heart disease, inflammatory biomarkers and other vascular risk factors,” he explained.

“We integrated the data from these studies of the genetic variant and associations with heart disease, with the data on blood levels of the IL-6 and IL6R proteins and associations with heart disease from the ERFC, and tried to understand a bit more of the story.” The study, published in March 2012 in The Lancet, suggests that IL6R-mediated pathways are causally related to coronary heart disease.

“The results suggest that if you want to intervene to lower CVD risk, one option might be to reduce the signalling of the IL6 pathway,” he said. “What is interesting is that there is already a drug on the market targeting this particular pathway, currently for the treatment of rheumatoid arthritis.” This finding heralds a new, more targeted and thus potentially more cost-effective approach to drug development for therapeutic intervention.

A complementary approach being used by the CEU is to measure hundreds of thousands of genetic variants, suggested as being of potential relevance to heart disease, at the same time using microarray technology. A new consortium will deliver results of a ‘mega-analysis’ of more than 200,000 genetic variants in coming months, helping to define those variants most strongly associated with CVD. And, by 2013, further microarray studies carried out by Butterworth and colleagues are expected to yield information on more than 200,000 additional genetic variants, many that are much rarer than those previously studied.

The work of the CEU has had a considerable impact on public health, clinical guidelines and priorities for medicines development in cardiovascular disease, as Danesh explained: “Through studies such as the ERFC, we are not only building on previous findings but also producing results that are robust enough to be applied to public health interventions.”

This research is funded by the British Heart Foundation, Medical Research Council, and National Institute of Health Research Cambridge Biomedical Research Centre.

Professor Peter Jones, Director of the Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough (CLAHRC CP), cites this young man as an example of one of the many highly vulnerable people who must traverse what he describes as pinch points in mental health services: “such gaps, despite vast efforts on the part of those carrying out the services, can sometimes place individuals with mental health problems in an impossible situation.”

Each year, around one in four adults in Britain will experience some kind of mental health problem, a condition that also affects children and the elderly. CLAHRC CP, a five-year, £23 million collaboration between the University of Cambridge, the National Institute for Health Research (NIHR) and six health and social care providers (see panel), is focusing applied health research on the urgent needs of patients at the front end of mental health service delivery. Three years into the CLAHRC, the work is having demonstrable beneficial outcomes to patients and clinicians.

Found in translation

CLAHRCs (there are nine around the country) have their origins in the 2006 Cooksey Review commissioned by the UK government, which identified two major gaps in the translation of health research into health care: the translation of basic research into products (often called ‘bench to bedside’ or type 1) and the implementation of these products into clinical practice (type 2). CLAHRCs, funded by the NIHR, were established to bridge the type 2 gap.

It’s not a straightforward matter, as Jones explained: “The type 2 gap involves a great many players and an understanding of how to move ideas around a system. In fact, it’s a sophisticated systems engineering and management problem.”

No wonder that Jones attributes a crucial part of the success of CLAHRC CP to the involvement of Cambridge’s Engineering Design Centre (EDC), Judge Business School (JBS) and Institute of Public Health: “We can look back now and see that much of our thinking began to change in the early stages as a result of these cross-cutting conversations. What we’ve learned is that there are principles to short-circuiting having an idea and getting it into the hands of people who can use it.”

Invention to innovation

The research strands of CLAHRC CP focus on the mental health of children and adolescents, adults with disorders, and old-age and end-of-life care (see panel). “Much of the research is highly technical but with close co-operation between researchers and the consumers – patients, clinicians and service managers – we’ve been able to make sure the findings are rapidly available and implemented,” explained Jones. “You could say that co-production is the essence of CLAHRC.”

Many of the research projects (26 at last count) demonstrate how involving consumers at an early stage not only helps to shape the work but also enables the consumers to plan for implementation. Jones likens the situation to a process in which the research is ‘pulled through’ by the end user: “When you have liaised with the consumer very early on, you know that their question is your question and they’re eager for your results.”

One example has been the Transfer of Care at 17 (TC17) study led by Professor Ian Goodyer, aimed at understanding the factors that facilitate or hinder successful outcomes when young people leave the care of the local authority. Adolescence is a complex period of rapid change for all young people but it’s also a critical period of vulnerability for developing mental health problems: approximately 50% of all lifetime mental disorders begin in the middle teenage years and 75% by the mid-twenties.

After discussion with Cambridgeshire Social Services, the TC17 researchers realised that describing the mental health needs of children in care was almost completely unchartered territory. Little was known of mental illness influences on personal and social adjustment in those leaving care, and adolescents revealed a reluctance to seek help. In association with young people, the team developed a tool to assess barriers to care and, partly in response to the findings, Cambridgeshire Social Services are undergoing a restructuring exercise to cater for 44 new units with an emphasis on family well-being and mental health.

The project has also led to the development and piloting of a new mental health training package for foster carers to help them identify core symptoms of emotional distress through close observation during a child’s first two weeks in care. “Both Cambridgeshire County Council and Peterborough County Council are enthusiastic about the pilot, along with the Looked After Children Psychology Service,” explained Goodyer. “If the results are positive it could lead to a fundamental change in how the foster carers are educated and supervised to help children in their care.”

“The greatest impact of the CLAHRC to date has been, and continues to be, the gradual enlightenment on the part of our local authority, voluntary sector and clinical colleagues of the potential value of high quality research to their work,” added Jones.

The main aim of CLAHRC-CP is to increase the value of services and what they can do for patients and their families. Often, improved services also result in cost savings, as is the case for the outcome of a research project on Improving Access to Psychological Therapies (IAPT).

The IAPT programme, provided by the NHS, offers psychological therapy to people suffering from mild to moderate depression and anxiety disorders, where previously medication and a long wait on a list for a counsellor had been the only option for GPs. Each year in England, mental health conditions cost approximately £105 billion due to loss of earnings and associated treatment and welfare costs.

Working with the East of England Strategic Health Authority, CLAHRC researchers, led by Jones, investigated whether the programme was meeting the needs of the local population. Having analysed data from over 100,000 consultations, the team showed that simply offering therapy by telephone rather than face to face was just as effective and yet much more cost-effective and convenient. It also opened up the service to people otherwise unable to access support owing to their remote location, physical disability, employment status or their avoidance of talking about their condition in person.

Alison Watson, IAPT Research Associate, explained the impact of the study: “It’s definitely a case of invest to save. For every patient who recovers from depression or anxiety, the NHS is saving over £1,000. IAPT is designed to prevent that ‘revolving door syndrome’. People are taught the skills to self-manage their condition, which leads to long-term sustained recovery. Access to the talking therapies over the telephone has been a real innovation in service delivery, which has helped services meet the needs of their local population.”

Boundary spanners

Ultimately, the key to translating invention into innovation sustainably, believes Jones, are boundary spanners – individuals who can understand both research and clinical practice. The CLAHRC Fellowship scheme, developed over the past year, has now trained 27 individuals from health and social care in research methodology, service redesign and change management. Already CLAHRC Fellows are making an invaluable contribution, acting as local ‘research champions’, and helping the CLAHRC connect with health care practitioners in the community.

Looking forward, Jones reflected on what he finds most exciting about the CLAHRC: “It’s the ability to be reactive to co-production and to be flexible enough to take on emerging areas in mental health, because if the consumers really want an answer, then it will happen more quickly and you’ll have more impact.”

Diet and activity behaviours, together with alcohol and tobacco, are risk factors for the world’s fastest growing health epidemic: a group of ‘silent killers’ that often develop slowly over many years and are known as the non-communicable diseases (NCDs).

NCDs, so-called because they are not transmitted person to person, include diabetes, cardiovascular disease, chronic respiratory disease, cancer and mental health disorders, and are by far the leading global cause of death. Of 57 million deaths recorded worldwide in 2008, NCDs were responsible for 36 million, 80% of which were in low- and middle-income countries. By 2030, the total number of NCD-related deaths could rise to 52 million and result in a cumulative loss in global economic output of $47 trillion.

The statistics are deeply shocking. But, as Professor Nick Wareham, Director of both the Medical Research Council (MRC) Epidemiology Unit and Cambridge’s Centre for Diet and Activity Research (CEDAR), explained there are potential solutions: “Behaviour is a key risk factor for NCDs, often closely connected with biological, environmental and social factors. With a more supportive environment and the right incentives, individuals might be more able to change their behaviour to look after their own health: taking exercise, eating a healthy diet, not smoking and limiting alcohol consumption.”

“As well as ensuring that high-risk individuals get the right support, we need effective strategies for targeting whole populations,” he added.  “The challenge is to discover what determines the population distribution of health-related behaviours so that we can understand how those distributions can be shifted.”

Research in a changing world

CEDAR is intent on building the evidence base on which to move populations in the right direction. Hosted by the Cambridge Institute of Public Health, the Centre is a partnership between the Universities of Cambridge and East Anglia, and the MRC Epidemiology Unit, the MRC Biostatistics Unit and the MRC Human Nutrition Research Unit. Created in 2008, it is one of five UK Public Health Research Centres of Excellence funded with a total of £20 million over five years by the UK Clinical Research Collaboration.

One of the efficiencies of the CEDAR approach is that it enables new studies to be overlaid on the foundations of some remarkably long-running, large-scale epidemiological studies carried out by the University and embedded MRC Units. The European Prospective Investigation of Cancer (EPIC)-Norfolk study, for instance, has been studying  25,000 individuals for almost 20 years to understand not only the connection between diet and cancer but also the factors that are most often present when people stay healthy throughout life. “Many of these factors might be obvious but you actually have to demonstrate their benefit or their risk so that interventions are based on empirical data,” explained Wareham.

Measuring the determinants of behaviour and evaluating interventions lie at the heart of the portfolio of projects at CEDAR. One study, SPEEDY, has been focusing on the factors that determine diet and physical activity in childhood and adolescence, a period that shapes behaviours that can last a lifetime. Among the findings of the project, which is funded by the National Prevention Research Initiative (NPRI), is the importance of the ‘physical activity friendliness’ of the school environment. One, perhaps counter-intuitive, finding is that allowing children to play outside in wet weather during school break times is associated with lower activity levels than keeping them indoors and providing opportunities for physical activity. This has implications for school policies on indoor play and the design of school grounds for wet weather.

Through systematic reviews of the evidence and a new randomised trial, CEDAR and the MRC Epidemiology Unit is also learning about how we can prevent childhood obesity by intervening during infancy. UK surveys have shown that more than one in five children are overweight or obese by the time they start school. “Little research has looked at how best to protect the health of bottle-fed babies, who gain weight rapidly and tend to be at higher risk of childhood obesity,” said Wareham. It turns out that many mothers lack information about how best to bottle-feed their babies and mistakes in feed preparation are common. CEDAR has developed a behavioural intervention aimed at parental feeding which is undergoing evaluation in a randomised controlled trial funded by the NPRI.

Some aspects of behaviour are shaped by the environment, including the layout of the buildings we work in or the infrastructure that determines how we travel to work. CEDAR researchers are interested in so-called natural experimental studies, which examine the effects of changes in the environment and policy on physical activity. The Commuting and Health in Cambridge study, funded by the National Institute for Health Research, is assessing whether the provision of new transport infrastructure such as the Cambridgeshire Guided Busway has any effect on travel behaviour and physical activity in the commuting population. The Busway only opened in summer 2011 but results gathered during the ‘before’ period are already providing insight into the factors that influence people’s travel behaviour.

“It might be that the biggest influences on the population’s diet and activity won’t just come from simply urging people to change,” explained Wareham. “Instead, major whole-scale restructuring of the way society operates might be necessary – from increasing access to green spaces, changing schools’ food policies to rethinking the physical structure of road networks.”

Capacity, research, translation

Building research capacity is a key aim of CEDAR, and currently 35 researchers with expertise in biostatistics, epidemiology, behavioural science, health economics, health geography and public health nutrition contribute to the work of the Centre. Another aim is to make evidence available in a form that is most usable to policy makers, through physical products such as evidence briefs and evaluation toolkits, and through developing relationships in policy and practice arenas.

Helping to facilitate the translation of research to policy, CEDAR works closely with the Eastern Region Public Health Observatory, which provides information, data and intelligence on people’s health and health care for practitioners, policy makers and the wider community.

Some CEDAR investigators also work as part of the newly formed Behaviour and Health Research Unit (BHRU), which is funded by the Department of Health Policy Research Programme to contribute evidence on effective ways of changing behaviour in populations to improve health and reduce health inequalities. Policy makers are currently showing great interest in ‘nudge’ approaches – altering environments to prompt healthier behaviour, without banning particular choices – and last year the BRHU questioned whether such an approach stands up to scientific scrutiny. We know from past examples that firmer legislative approaches can reap dramatic health rewards: when Scotland first imposed a ban on smoking in public places in 2006, a 17% reduction in admissions for heart attacks was recorded within a year across nine Scottish hospitals. But questions remain about which interventions are the most cost-effective and worthwhile – the so-called ‘best buys’.

“The increasing number of people with NCDs is a vast public health and economic problem. Although it is widely accepted that something needs to be done, there is uncertainty about how this epidemic can be stemmed,” said Wareham. “At the moment, the sound base of research underpinning solutions is largely lacking. There may be some policies that could be put in place now but we believe that interventions should be better evaluated. Going forwards, the scale of the task we face globally is huge. CEDAR has already made a good start.”

Yet compared with cot death, rates of stillbirth have fallen little over the past decade. And whereas women now have access to sophisticated screening for Down’s syndrome, the way we screen for stillbirth still relies on little more than a tape measure. According to Professor Gordon Smith of the Department of Obstetrics and Gynaecology: “When we think of serious complications of pregnancy one of the most common is stillbirth. But if you look at how we screen for stillbirth, for the general low-risk population – which is the population that has most stillbirths because there are more of them – the only currently recommended way of screening is measuring the size of the uterus with a tape measure.”

For parents, a stillborn baby is tragedy. Many of these tragedies could be prevented given better ways of predicting which women are at most risk. Which is why in 2008 Professor Smith set up the Pregnancy Outcome Prediction Study (POPS).

One the largest and most robust studies of its kind, the four-year, National Institute for Health Research (NIHR)-funded study involves more than 4,000 volunteers – women in their first pregnancies who agree to take part in the research when they book their first scan at the Rosie Maternity Hospital in Cambridge. Having currently recruited 4,200 women, the project is on target to reach a total cohort of 4,500 by July 2012.

As well as their routine ultrasound scans at 12 and 20 weeks, the women have blood tests, and additional research scans at 28 and 36 weeks, and when they give birth a sample of the placenta is kept and stored. Combining all this information will, Professor Smith believes, provide a clearer picture of how best to identify women at increased risk of stillbirth.

“The aim of POPS is to try and identify whether there’s a combination of ultrasound and biochemical markers that better predict high-risk pregnancy, and which when applied in a screening programme would reduce the number of stillbirths,” he said.

“The basic premise is that by studying the placenta and comparing it with controls, we can identify the things which are different in the placenta of a complicated pregnancy. And the rationale for studying the placenta is that there’s a great deal of evidence to indicate that many stillbirths are related to an abnormal placenta.”

Knowing which women are at higher risk of stillbirth would allow clinicians to decide how best to intervene to reduce that risk. “Initially, we would see this information being used to predict complications at term, 37 weeks and beyond, which is when one third of stillbirths occur,” Professor Smith explained.

“One of the key things for me is the prospect of intervention, and the most obvious intervention is to deliver the baby early. Stillbirth often results from a diseased placenta so it’s hard to treat, but once a woman reaches the 37th or 38th week of pregnancy you have the option of inducing labour,” he said.

“Or it might be that we simply monitor the baby continuously during labour, or advise against certain women giving birth at home or in a midwife-led unit.”

Cambridge is ideally placed to conduct a study like POPS. As well as having hundreds of willing volunteers, “Cambridge is probably the strongest centre in the world for people with an interest in the biology of the placenta,” explained Professor Smith. “We also have the Centre for Trophoblast Research, which brings together clinical and non-clinical researchers working on the placenta, and we have close links with the School of Biological Sciences, the Gurdon Institute and the Babraham Institute.”

The funding from NIHR to create the resource has enabled Smith to leverage additional support; the project currently receives funding from the Wellcome Trust, the Medical Research Council, British Heart Foundation, and the Stillbirth and Neonatal Death Society.

Coupled with great researchers, Cambridge excels in clinical research design, without which developing screening to reduce stillbirth would be impossible, he said: “Good scientists need well-defined material to study, and what we have in POPS is real excellence in clinical research design coupled with excellent basic science.”

If the results from POPS do identify ultrasound and biochemical markers that predict risk of stillbirth, the next stage would be a trial to test the effectiveness of the screening and intervention. “The ultimate aim would be for our work to become part of a NICE guideline, changing the antenatal care women receive,” he said. “It’s early days but our initial analysis looks very promising.”

Unlike white fat, which functions primarily to store up fat, brown fat (also known as brown adipose tissue) burns fats to generate heat in a process known as thermogenesis.  The research, led by scientists at the University of Cambridge Metabolic Research Laboratories at the Institute of Metabolic Science, discovered that the protein BMP8B acts on a specific metabolic system (which operates in the brain and the tissues) to regulate brown fat, making it a potential therapeutic target.

The scientists believe that activating brown fat could help to support current weight loss programmes, which individuals often struggle to maintain.

Dr Andrew Whittle, one of the authors of the paper from the Institute of Metabolic Science, said: “Other proteins made by the body can enhance heat production in brown fat, such as thyroid hormone but often these proteins have important effects in other organs too. Therefore they are not good targets for developing new weight loss treatments. However, BMP8B seems to be very specific for regulating the heat producing activity of brown fat, making it a more ideal mechanism for new therapies.”

The experiments showed that when mice lacked the protein BMP8B they found it more difficult to maintain their normal body temperature. They also became much more obese than normal mice, particularly when fed a high-fat diet.  Additionally, when the researchers treated brown fat cells with BMP8B they responded more strongly to activation by the nervous system. Furthermore, when BMP8B was administered to specific parts of the brain it increased the amount of nervous activation of brown adipose tissue.  The result was that these BMP8B-treated brown fat cells burned more fat and mice given BMP8B in the brain lost weight.

Professor Toni Vidal-Puig, lead author of the study from the Institute of Metabolic Science and a member of the MRC Centre for Obesity and Related Metabolic Diseases, said:  “A major feature of current weight-loss strategies is that people lose a lot of weight early on, but then reach a plateau despite continuing to follow the same diet regime. This is because the human body is incredibly good at sensing a reduction in food consumption and slows the metabolic rate to compensate. A strategy to increase brown fat activity could potentially be used in conjunction with current weight loss strategies to help prevent the typical decrease in a person’s metabolic rate.

“One could be sceptical that techniques to increase metabolic rate might just be compensated by the body trying to make you want to eat more, to fuel this increased metabolism. But our findings showed that treating mice with Bmp8b did not have this effect, it simply made them lose weight by burning more fat in their brown adipose tissue.

“There are obvious differences between mice and humans, and from a therapeutic perspective this work is preliminary. Validation will be necessary to see if manipulating BMP8B would be safe and effective in humans.”

The research was funded by the Medical Research Council (MRC), the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council (BBSRC).

However, according to a report published by the National Audit Office in 2010, there is too little joined-up working between health and social care services for people with dementia, a situation echoed by Professor Carol Brayne, Director of the Cambridge Institute of Public Health (CIPH): “What patients and families tell us is that there are problems with fragmentation of care for dementia, with not enough information about what’s available and what pattern of services works best.”

Brayne and colleagues within CIPH (see panel), together with collaborators from Cambridgeshire and Peterborough NHS Foundation Trusts and partners from the Cambridge University Health Partnership, realised that a new approach was needed to underpin the delivery of improved dementia care, as well as to further research on dementia screening, treatment and prevention. Their aim is to build a dementia registry to support both service and research.

Evidence road map

“Until now, not enough of the research evidence cited in dementia guidelines has been generated on the populations to whom the treatments will be applied – the older old, aged 80 and above,” explained Brayne. “This could be resolved by an up-to-date dementia registry based on the systematic collection of all data relating to individual patients with dementia combined with a road map of evidence, both qualitative and quantitative, right the way through from prevention to palliative care.”

Physicians and public health specialists need accurate and up-to-date data to compare therapies, reduce risks and set standards, and in recent decades registries have become a key part for monitoring illnesses such as cancer, infectious disease and diabetes. Because registries contain information on patient history, diagnosis, treatment and social care, they are valuable not only for making important public health decisions about treatment and co-ordinated care but also for identifying gaps that require further research.

The complex process of designing and delivering a registry for dementia in Cambridgeshire and Peterborough has now begun. It aims to be the first truly population-based register nationwide to link all services in the area. Developing a registry is not without its challenges, as Brayne, who chairs the steering committee, explained: “There are very important data governance and social and ethical issues to address, including the label itself – not everybody who might meet the criteria for dementia would wish to call themselves demented. It’s a very emotive label and there’s a lot of fear. One of things we want to do is help with destigmatisation.”

After a scoping study commissioned by the Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough (CLAHRC CP), work began last year to develop the system and the first phase of the registry is under way, working with primary and secondary care.

Two phases that will sit alongside each other have been planned: one (now in active development) is a care pathway registry to link data directly from GPs relating to various stages in the patients’ journey through inpatients, outpatients, community care and related services; and another will create a research registry of people with dementia who are suitable, and would welcome the opportunity, to participate in research. Both phases have the backing of the National Institute for Health Research (NIHR) Dementias and Neurodegenerative Diseases Research Network, which is also actively supporting the development of registers nationwide, and now endorsed through the Prime Minister’s Challenge.

“The previous lack of a dementia register across the Cambridgeshire and Peterborough areas has meant there has been limited information for planning services,” added Brayne. “Going forward, stakeholders will be able to monitor trends and plan ahead for the ageing population. We hope this initiative will also improve safety and efficacy of day-to-day clinical management for people with dementia, improve outcomes and maximise efficiency.”

Data for health

The dementia registry is one element of  a more ambitious vision: to integrate data with health care planning and research for a whole range of common chronic diseases “so that doctors have the right information at the right level in front of them, and researchers have the appropriate permission to recruit patients for research studies.”

Dementia is a current priority but, long term, what Brayne and colleagues are calling Data4Health Cambridgeshire will draw from CIPH’s work on conditions such as cancer, cardiovascular disease, neurodegenerative diseases, osteoporosis and metabolic diseases, and hope to join this all the way through to local authorities and voluntary sectors. The work of CIPH partners such as the Eastern Region Public Health Observatory and Eastern Cancer Registration and Information Centre will be crucial to push forward health information sharing for care policy and research.

“The key benefit of this approach is that results from world-class researchers are immediately open to the assessment of their impact on a population,” explained Brayne. “For instance, for dementia, we have a well-established programme of ageing and neuroscience research across the University. Data4Health will feed into these programmes and be fed by them.”

Examples include research in the Biomedical Research Unit in Dementia and the Cambridge Centre for Brain Repair on the molecular basis and potential for screening and treatment of neurodegenerative diseases;  research at the Cambridge Centre for Ageing and Neuroscience on how individuals can best retain cognitive abilities into old age; and longitudinal studies, some of which began running in the 1980s, led by Brayne at CIPH and colleagues in the Department of Psychiatry to investigate depression, physical disability and early detection of dementia. In addition, researchers in the Behaviour and Health Research Unit and in the Centre for Diet and Activity Research are gathering evidence on life-course behaviours that optimise the chance of a healthy old age.

“Crucial to the success of the registry,” added Brayne, “is allowing the whole population to become part of the enterprise. They can become more familiar with the benefits of a research and experimental approach to generating knowledge, and ultimately they can seek to drive it themselves – as true partners in the process of public health research and action.”

The British Heart Foundation (BHF) funded project, a collaboration between scientists from the Universities of Cambridge and Edinburgh, is the first to demonstrate the potential of combined PET and CT imaging to highlight the disease processes causing heart attacks directly within the coronary arteries.

The research, published last week in the Journal of the American College of Cardiology (JACC), involved imaging over 100 people with a CT calcium scan to measure the amount of calcified or hardened plaques in their coronary arteries. This is a standard test, which is commonly used to predict heart attack risk but cannot distinguish calcium that has been there for some time from calcium that is actively building up.

The patients were also injected with two contrast agents that show up on PET imaging scans, and which can be used to track various metabolic pathways in the body. One of these tracers, 18F-sodium fluoride (18F-NaF), is a molecule taken up by cells in which active calcification is occurring. The 18F-NaF can then be visualised and quantified during a PET scan.

The researchers wanted to see if they could identify patients with active, ongoing calcification because these patients may be at higher risk of heart attack than patients in whom the calcium developed a long time ago. The results showed that increased 18F-NaF activity could be observed in specific coronary artery plaques in patients who had many other high-risk markers of cardiovascular disease.

Dr James Rudd, HEFCE Senior Lecturer at the Department of Medicine and joint senior author of the paper, said: “Our results show, for the first time, that certain areas of atherosclerosis within the coronary arteries, previously thought to be inert, are actually highly active and have the potential to cause heart attack. Once identified, they might be targeted with drug therapy more effectively.

“Additionally, we might be able to improve our ability to predict an individual person’s future risk of heart attack using this fairly straightforward imaging test in selected people.

“This research exploits longstanding scientific links between my research team in Cambridge and Professor Newby’s in Edinburgh, with core support from the Cambridge NIHR Biomedical Research Centre, HEFCE and the British Heart Foundation.”

Dr Marc Dweck, lead author on the research paper and a BHF Clinical Research Fellow at the University of Edinburgh, said:

“Predicting heart attacks is very difficult and the methods we’ve got now are good but not perfect. Our new technique holds a lot of promise as a means of improving heart attack prediction although further ongoing work is needed before it becomes routine clinical practice.

“If we can identify patients at high risk of a heart attack earlier, we can then use intensive drug treatments, and perhaps procedures such as stents, to reduce the chances of them having a heart attack.”

Dr Shannon Amoils, Research Advisor at the (BHF), which funded the study, said:

“For decades cardiologists have been looking for ways to detect the high-risk plaques found in coronary arteries that could rupture to cause a heart attack, but it’s been difficult to develop a suitable imaging test that can focus in on these small vessels.

“This research is a technical tour de force as it allows us to assess active calcification happening right in the problem area – inside the wall of the coronary arteries and this active calcification may correlate with a higher risk of a heart attack.”

There are nearly 2.7 million people living with coronary heart disease (CHD) in the UK and it kills 88,000 people each year. Most of these deaths are caused by a heart attack. Each year there are around 124,000 heart attacks in the UK.

Melioidosis is caused by Burkholderia pseudomallei, a bacterium that resides in the soil of Southeast Asia and northern Australia. In some locales, the number of people who die after developing melioidosis is as high as 40%, and in northeast Thailand it causes as many deaths as does tuberculosis. What makes the disease so menacing is that not only is the bacterium resistant to all but a narrow range of antibiotics but it is also frequently under- or misdiagnosed, with fatal and often rapid consequences.

Yet, according to Cambridge scientist Professor Sharon Peacock, a world expert on melioidosis, this infection and its related deaths are potentially preventable. Not through vaccination (indeed, none exists) but through simple public health measures. “Because individuals acquire infection after contact with soil containing the pathogen, and not from person-to-person contact, it’s potentially avoidable through behavioural changes,” explained Peacock. “Simple guidelines that make people aware of the risks associated with certain activities could ease a major disease burden.”

Although much progress has been made in the past decade towards understanding how the bacterium causes disease, little is known about the global distribution of the bacterium in the environment, and therefore where people (including travellers) are at risk. In addition, the US Centers for Disease Control and Prevention has classified the bacterium as a Category B ‘select agent’ (potential biological weapon). Preparedness against melioidosis in the event of a deliberate release has therefore become a security concern.

Peacock has been working in collaboration with a team led by Dr Direk Limmathurotsakul, Deputy Head of Microbiology at the Wellcome Trust Major Overseas Programme in Thailand, to trace the routes of infection for melioidosis. Their aim has been to drive down the incidence of disease by providing the first evidence-based guidelines worldwide for its prevention.

‘Tip of the iceberg’

Although melioidosis was first described in 1911 in Burma, the disease has been little studied over the past century. Not until US soldiers returned home infected with the bacterium after their service in Vietnam did the disease begin to attract attention in the West. Even then, the disease was largely regarded as chronic rather than acute – patients tended to develop symptoms so long after acquiring the infection that it became known as the ‘Vietnamese time bomb’.

Only since the 1970s has melioidosis begun to be taken seriously as a public health threat in Southeast Asia, said Peacock: “It’s been a hidden disease – we’re only really now seeing what many believe is the tip of the iceberg in terms of numbers of people infected.” Under-reporting, she believes, is the consequence both of it taking up to a week to diagnose the disease by culturing the bacterium in a microbiology lab, and of the scarcity of such diagnostic facilities across the region.

Misdiagnosis is common because melioidosis can cause infected individuals to present with a wide range of clinical manifestations. Unhappily, in the absence of an accurate diagnosis, the specific and long-term antibiotic treatment the patient requires is rarely given, and death occurs swiftly from severe sepsis and associated organ failure. “The single most important objective therefore has to be to prevent people from acquiring the disease in the first place,” asserted Peacock.

Inoculation, ingestion, inhalation?

Peacock, Limmathurotsakul and colleagues have now completed the first prospective hospital-based case-control study in Asia to identify what aspects of daily living put individuals at risk of B. pseudomallei infection.

“Current advice in northern Australia, where melioidiosis is also common, includes avoiding contact with soil and washing hands and feet. But this is largely based on common sense rather than evidence, and compliance and efficacy are unknown,” explained Peacock, whose research was funded by the Wellcome Trust. “In Asia, no advice is given to people living in melioidosis-endemic areas. A programme of prevention could be relatively inexpensive, readily implementable and applicable to all.”

Over an 18-month period, patients presenting to hospital with melioidosis were recruited to the study. Using a questionnaire and home visits, the team have been tracing the route of infection – investigating whether disease has resulted from inoculation through abrasions in the skin, ingestion of water and food, or inhalation of aerosols – and using genotyping to define the bacterial strains present in the patients and environment.

“There are major knowledge gaps in Asia regarding the frequency with which water supplies are contaminated with B. pseudomallei simply because no-one has looked before,” explained Peacock. “We are also uncertain whether being outside during severe weather could be a risk factor associated with inhalation of the bacterium.”

The results of the research have been collated and a set of guidelines will be developed and disseminated to a network of public health officials. The main recommendations are likely to be to not drink untreated water, to avoid exposure to severe weather, and for agricultural workers to use protective clothing and footwear. Now, Limmathurotsakul and colleagues are developing a public engagement campaign to raise awareness of melioidosis in Thailand.

A previous study by Peacock and colleagues has shown that another strong risk factor for melioidosis is diabetes, which puts individuals at a vastly increased risk of B. pseudomallei infection. Given that the prevalence of diabetes is rising in Thailand, an additional aim is to provide public health guidance targeted towards education programmes in diabetic clinics.

Thinking globally

The team are now widening their scope to consider other regions of Asia and the world. Melioidosis is known to occur in areas of Southeast Asia such as Laos and Cambodia, but incidence rates are poorly defined and may be grossly underestimated, as Peacock highlighted: “It was very telling that the first time it was realised that melioidosis was in Laos was when the bacterium was cultured from the soil in 1998. Once detected, a study was carried out in the capital and within a few years several hundred cases had been diagnosed.”

“We predict that melioidosis will become recognised as a major pathogen throughout this region in the wake of laboratory strengthening and use of standard guidelines,” she added.

Worldwide, the paucity of information about the geographical distribution of the organism has meant that there is an incomplete global risk map, with vast regions of the world completely unmapped, including Indonesia, India, Africa and most of South America. Peacock and colleagues have initiated an international working party that will facilitate the mapping process. First, however, they had to devise consensus guidelines on how to carry out soil sampling using the simplest and cheapest of techniques, to maximise use in resource-poor settings. Guidelines have now been agreed and the team is in the process of developing a website (www.melioidosis.info/) from which protocols for sampling can be downloaded, and complete data from sampling studies can be deposited to build a global map of the distribution of environmental B. pseudomallei.

Melioidosis has recently been described in southern India, and soil-sampling studies are under way there. With the support of the Cambridge-Hamied Visiting Lecture Scheme,  Peacock has been working with researchers at Kasturba Medical College, Karnataka, India, to provide practical advice and knowledge on environmental sampling. Local initiatives will enable researchers in the region to monitor, manage and reduce the effects of an emerging infectious disease.

“These initiatives in Thailand and India have the potential to reduce the impact of an emerging infectious disease,” Peacock explained. “While the true incidence of melioidosis is unknown, it is likely that many millions of people are repeatedly exposed to B. pseudomallei.”

Its success is clearly related to the availability and progress of medical interventions. But its success is also related to innovations in agriculture, architecture and engineering, and a deeper understanding of the social science of behaviour and many other areas. Public health is a truly multidisciplinary undertaking, which is why in Cambridge we have recently created PublicHealth@Cambridge, a Strategic Network that draws together 300 researchers from the arts, humanities, social sciences, technology and biomedicine who have an interest in public health.

The need for public health research is as great as ever. Longer life means a rise in dementia and other diseases associated with ageing. The emergence of epidemics of non-communicable disorders such as cardiovascular disease, cancer, chronic lung diseases and diabetes, which kill three in five people worldwide, pose challenges in the developed and developing world alike. And, re-emerging communicable diseases, resistance and the role of infection in chronic diseases are also public health concerns.

The cost of making poor decisions about public health will have profound consequences and necessitates some tough questions to be asked: can we alter health outcomes by influencing whole societal structural change? How should investment in prevention be balanced with investment in treatment? How, and based on what evidence, do we implement new technologies? Will health systems provide affordable care for everyone everywhere?

Add to this the manifold changes taking place in English public health services and research, as the government sets out its vision for improving well-being across the whole population, it’s as critical to ensure that we draw on a rich mix of disciplines to inform public health as it is to align research to health, social care and commissioning provision.

Our vision for PublicHealth@Cambridge is to develop synergy across Cambridge in areas of public health importance such as international health, social and behavioural science and methodological advances. By co-ordinating research and activities, kick-starting new approaches and new programmes – from molecule to policy making, regional to global, campus to community – we aim to generate fresh insight into the health and well-being of populations.

All the cells in the body have the same DNA sequence (genome), but it is how this DNA sequence is interpreted that results in the formation of different cell types. Epigenetic changes control how a DNA sequence is interpreted, specifically how different genes are switched on and off in different cell types, tissues and organs.

One of the most studied epigenetic marks is the addition of a very small chemical modification called a methyl group to DNA, which turns associated genes off. Methyl groups are always added to the DNA base cytosine and so this chemical modification is called 5-methylcytosine (5mC). Babraham Institute scientists are involved in researching the role of another DNA chemical modification in mammals called 5-hydroxymethyl-cytosine (5hmC), which is believed to be important for stem cell function, helping to define how the body develops. 5hmC may be a separate epigenetic mark or possibly be part of the process which removes methyl groups from DNA, allowing genes to be switched on again. Decoding the ‘epigenome’ will provide greater understanding of how cells are regulated and has major implications for regenerative medicine and how cells such as stem cells can be controlled.

Professor Shankar Balasubramanian FRS, of the University of Cambridge Chemistry Department and Cancer Research UK Cambridge Research Institute, and his PhD student Michael Booth invented new chemistry to allow the recently discovered base 5hmC to be sequenced in DNA at single base resolution.  This was not possible using existing methods.  In a fruitful collaboration between the Cambridge group (led by Balasubramanian) and the Babraham Institute (led by Professor Wolf Reik FRS), this method was applied to sequence 5hmC and 5mC in embryonic stem cell genomic DNA.

Balasubramanian, whose group previously co-invented Solexa sequencing, explained, “Sequencing DNA is becoming an increasingly important part of science and medicine and we are pleased to have met the challenge of finding a way to sequence this important new base modification.”

Michael Booth, co-inventor of the technique, said, “We developed a chemistry that was specific for this new modified DNA base, 5hmC. This allowed us to accurately distinguish between 5mC and 5hmC at single base resolution in the genome.”

Dr Miguel Branco from the Babraham Institute who is joint lead author commented, “There was a real need in the field for a technique that would map both 5hmC and 5mC in the genome quantitatively and at high resolution. We applied this new technology to embryonic stem cells and immediately recognised its power in furthering our understanding of the biological functions of these DNA modifications.”

Professor Wolf Reik who led the study at the Babraham Institute, which receives strategic funding from the Biological Sciences Research Council (BBSRC) said, “It has recently become apparent that in addition to DNA methylation, there are other modifications of DNA, such as for example hydroxymethylation. This suggests that DNA modifications are more dynamic than we previously thought. With the new method we are now in a position to map these modifications at great precision, and to relate them to stem cell function, ageing, and perhaps more generally to how the environment interacts with the genome.”

The Babraham Institute undertakes world-leading life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Professor Michael Wakelam, Director of the Babraham Institute, said, “This is an excellent example of collaboration between research institute and University research scientists. The work will improve our knowledge of how cells develop, with potential long-term benefits to society.” In addition to the BBSRC, this research was supported by the MRC, the Wellcome Trust and the EU.

Professor Daan Frenkel ForMemRS, Head of the Department of Chemistry at the University of Cambridge, commented, “This new technique, which reflects the continued innovative work of Professor Balasubramanian and his team, will dramatically change how epigenetic research is conducted.  By collaborating with experts at Babraham, they have also demonstrated how the technique will have significant implications for regenerative medicine.”