The Computational Medicine Research Team has pioneered applications of NMR-based metabolic profiling in epidemiology and genetics. This stems from long dedicated research in the Team during the past ten years on developing and optimizing an NMR-based metabolomics platform for human serum. Along with the experimental development and automation, the Team has worked intensively to automate the data analyses and absolute metabolite quantifications. The resulted platform is unique both in its quantitative molecular output (>200 metabolic measures) and cost-effective high-throughput (analysis costs comparable to routine lipid clinical chemistry).
Using the serum NMR metabolomics platform, we have now analysed close to 200,000 samples from over 20 epidemiological cohorts and biobanks. All these data have been acquired using two platforms in Finland, one operational since January 2009 and the other since February 2013. Based on the present funding and strategic decisions, at least six additional platforms are expected to be up and running in Finland and in the United Kingdom by the end of 2015. The new machines will increase the total capacity of the platform analyses to over 250,000 samples per year. The UK institutions joining the global laboratory network are the University of Bristol (2 NMR machines), University of Glasgow (1), University of Oxford (1), and University College London (1-2).
The established and expanding collaborative network is pioneering and aims for global population coverage and life-course understanding of systemic health and disease aetiologies. This collaboration is leading to an unprecedented amount of coherent quantitative molecular data on systemic metabolism and will allow tackling key research questions and very large-scale analyses not otherwise feasible.
UK Medical Research Council has awarded £10.5M funding for the new MRC University of Bristol Integrative Epidemiology Unit (IEU). The MRC funding is supplemented by £12.5M from the University of Bristol.
IEU was established 1 June 2013 and the first funding period will be 5 years. IEU is led by Prof George Davey Smith and it includes six interrelated research programmes:
UNITE involves a set-up of a Metabolomics Core Facility at the University of Bristol including two high-throughput NMR spectrometers initially focused to apply the serum NMR metabolomics platform developed by the Computational Medicine Research Team in Finland. Prof Ala-Korpela was one of the applicants being named as a key UNITE staff member and is leading the Metabolomics Core Facility at the University of Bristol.
Prof Davey Smith is a clinical epidemiologist whose research has pioneered (1) understanding of the causes and alleviation of health inequalities; (2) lifecourse epidemiology (3) systematic reviewing of evidence of effectiveness of health care and health policy interventions (4) population health contributions of the new genetics. He is currently Scientific Director of the Avon Longitudinal Study of Parents and Children (ALSPAC) – which is also known as Children of the 90s. More than 14,000 mothers enrolled during pregnancy in 1991 and 1992, and the health and development of their children has been followed in great detail ever since. The ALSPAC families have provided a vast amount of genetic and environmental information over the years. This resource is assisting scientists all over the world with research into a wide range of health problems.
The serum NMR metabolomics data are currently available for the ALSPAC kids at 7, 15 and 17 years of age (over 12,400 samples analysed) and for the ALSPAC mothers at two time poins (over 7,300 samples analysed).
The ALSPAC is a prospective cohort study with unprecedented scope and detail of information on thousands of people from before birth through to early adulthood, on their parents and now on their children. It is an internationally valued resource at the forefront of population-based research. ALSPAC allows the investigation of developmental trajectories marking critical periods in human life, the genetic and epigenetic factors contributing to health and disease and the environmental exposures that form the context within which these processes act. As ALSPAC participants enter adulthood and start having children, the study's potential to contribute to scientific discovery is expanding, giving a greater capacity to explore links between current and future health and the intergenerational components of health and disease. ALSPAC is unequivocally the richest open-access epidemiological resource in the world. The overall objective of ALSPAC is to understand how risk and protective factors - environmental, genetic, epigenetic, behavioural and socioeconomic - interact to bring about disease or maintain health in people across their lifecourse and across multiple generations.
Prof Hingorani is coordinating the UCLEB Consortium for the development of a population -omics resource for stratification, prediction, causal analysis and drug development in cardiometabolic diseases. His team has recognised the key importance of datasets that integrate information on genotype, biomarkers and CVD end-points and assembled the University College -London School of Hygiene-Edinburgh-Bristol (UCLEB) Consortium encompassing 12 British cohort studies (e.g., the Whitehall-II, the British Women’s Heart and Health Study, the MRC 1946 Birth Cohort, and the 1958 Birth Cohort). The ~30,000 participants were recruited either at birth or in mid-life with prospective follow-up periods (from 7-65y). The UCLEB has detailed clinical and genetic metadata available and incorporates ~2,000 cases of prevalent and incident T2DM, and ~5,000 CVD events.
Prof Ala-Korpela will be coordinating the installation of a serum NMR metabolomics platform at UCL during 2014.
A research project entitled “Cardiometabolic disease prediction, causal analysis and drug development using high-resolution proton NMR metabolomics (The UCLEB consortium)”, led by Prof Hingorani, has been given (11/2013) a 3-year grant of approximately £800,000 from the British Heart Foundation. Prof Ala-Korpela is a co-applicant in the application.
The Computational Medicine Team in collaboration with the UCLEB Consortium has already serum metabolomics data available for the British Women's Heart and Health Study (n=3,829), the Whitehall II Study (n=6,204), the MRC 1946 Birth Cohort Study (n=1,809), and the Edinburg Type 2 Diabetes Study (n=1,058). The analyses for the British Regional Heart Study (n around 4,000) and for the UK Collaborative Trial of Ovarian Cancer Screening (n around 4,800) are under way.
Prof Sattar is interested in CVD biomarkers and diabetes-related research including work on obesity and related complications. He is also involved in several clinical trials in areas covering diabetes, obesity, and CVD risk.
With Prof Sattar we are currently collaborating on his two heart failure studies with baseline samples and subsequent end-points including very high mortality rates, i.e., very powerful prospective studies in an area of clinical need. Currently over 2,000 samples are available. Heart failure is associated with various metabolic abnormalities and high mortality even though many systemic metabolic characteristics are unknown. We have also started collaboration with randomised controlled drug trials, e.g., of the metabolic (vs. placebo) effects of metformin in non-T2DM patients with CVD (the CAMERA study).
Prof Ala-Korpela is coordinating the installation of an NMR metabolomics laboratory at the University of Glasgow, the BHF Glasgow Cardiovascular Research Centre; the serum NMR metabolomics platform is already up and running in a 600MHz instrument. An active collaboration is also on-going to develop a NMR-based quantitative metabolomics methodology to analyse cord serum samples.
The CAMERA study is a double-blind randomised placebo-controlled trial (RCT) examining the cardiovascular effects of metformin in stable coronary artery disease. It is a single-centre RCT of metformin vs. placebo over 1.5 years in men and women with stable coronary artery disease. The primary endpoint is change in common carotid artery intima-media thickness (cIMT).
Prof Kooner is leading the London Life Sciences Prospective Population Study (LOLIPOP). It has been running since 2002 and comprises detailed health assessments on more than 30,000 people living in West London (UK Indian Asian and European white subjects).
The Computational Medicine Team has been collaborating with LOLIPOP since 2009 and serum NMR metabolomics data have been obtained for all the ~30,000 individuals in LOLIPOP (almost 15,000 of which also have genome-wide data available).
The London Life Sciences Prospective Population Study (LOLIPOP) is a major UK research study investigating the mechanisms underlying heart disease stroke, diabetes, obesity and other major medical problems. The LOLIPOP study has been running since 2002 and comprises detailed health assessments on more than 30,000 people living in West London. These volunteers will be followed for many years. The LOLIPOP study is based at Ealing Hospital in West London, and at Imperial College London.
One of Prof Chaturvedi’s key scientific interests is ethnic differences in diabetes related mortality. She is leading a large tri-ethnic (European, South Asian and African Caribbean) cohort in the UK, using state of the art vascular imaging for subclinical vascular disease, and metabolic studies –the Southall And Brent REvisited (SABRE) study. Prof Hughes’ work focuses on the structure and function of the cardiovascular system in health and disease.
The Computational Medicine Team is collaborating with SABRE and we already have serum metabolomics data available for the baseline (n=3,593) as well as for the follow-up (n=1,426) samples.
The Southall And Brent REvisited Study (SABRE) is a longitudinal UK population-based study involving nearly 5,000 men and women. It is a multi-ethnic study aiming to compare cardiovascular disease and diabetes aetiology in people of European, Indian Asian and African Caribbean origins.
Prof Järvelin and Prof Keinänen-Kiukaanniemi are leading the Northern Finland Birth Cohorts, which are a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioural risk factors. The studies involve the use of two longitudinal cohorts of mothers living in the two northernmost provinces of Finland, with expected dates of delivery falling during two 1-year periods, the first, NFBC1966 between Jan 1 - Dec 31 1966, the second, NFBC1986 between July 1 1985 and June 30 1986. In both studies, mothers and children have been followed up since mothers enrolled at their first antenatal clinic visit.
Serum metabolomics is available for the NFBC66 (at the age of 31-y; n=~5,700) and for the NFBC86 (16-y; n=~5,600 / 19-y; n=~700). The clinical studies and sample collections for a new follow-up point has just been completed in the NFBC1966 (46-y; n~6,000) with serum (including an OGTT with 4 time points), urine, and faecal metabolomics planned (2014-2016).
Maternal health and neonatal environment has profound impact on health later in life. The Northern Finland Birth Cohorts were initiated to study these influences on disease risk factors, social wellbeing and long-term morbidity. The birth cohort studies are comprised of children born in the two northernmost provinces of Finland. The study population comprises almost all children born in the provinces of Oulu and Lapland during the years 1966 and 1986. Health examinations including blood sample collection have been conducted when the individuals were 31 and 16 years of age, respectively, with more than 6000 individuals in each follow-up. As the cohort participants have grown older the study purpose has expanded to investigate the genetic and environmental evolution of symptom variation and intermediate disease markers throughout the life-course. Metabolic profiling using NMR spectroscopy has been applied to the serum samples collected from both birth cohorts. The comprehensive data on metabolite levels allows unprecedented characterization of the metabolic signatures of cardiovascular risk factors such as obesity, insulin resistance and hypertension. The longitudinal design of the Northern Finland Birth Cohorts enables identification of high-risk groups and biological markers amenable to early intervention and prevention. The characterizing exposures and risk factors before disease onset make the studies invaluable for understanding the influence of environmental and hereditary factors and their interactions in complex diseases.
Prof Mark McCarthy leads a diabetes research group based at both the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) and the Wellcome Trust Centre for Human Genetics (WTCHG). The research of the group focuses, e.g., on the susceptibility gene identification in type 2 diabetes and related phenotypes (including obesity and continuous measures of glycaemia) using large-scale genetic and genomic approaches and translating gene identification into biological insights and clinical advances.
Prof Fredrik Karpe’s group is doing research on human adipose tissue function and metabolic consequences of obesity. His translational work is also much supported by the Oxford Biobank that he established in 2001. This currently includes over 5,000 healthy population-based 30-50 year old men and women resident in Oxfordshire. Participants have consented to be re-approached for a “recruit-by-genotype” participation in physiological studies of complex intermediary phenotypes.
Prof Collins's work has been in the establishment of large-scale epidemiological studies of the causes, prevention and treatment of heart attacks, other vascular disease, and cancer, while also being closely involved in developing approaches to the combination of results from related studies.
Prof Zhengming Chen’s research is focused on chronic diseases (e.g., heart disease, stroke, diabetes, COPD and cancer), which are the leading causes of disability and death in developed and developing countries. Several important causes of various chronic diseases are already known, but this knowledge is mainly based on studies in the West and does not suffice to explain much of the really large geographic differences in disease rates around the world. Large blood-based prospective studies, with detailed phenotyping and long-term follow-up, are needed to allow the reliable identification of other important causes of chronic diseases. In collaboration with the Chinese Academy of Medical Sciences (CAMS), Prof Chen has established one of the world's largest blood-based prospective studies of the environmental and genetic determinants of chronic diseases; the China Kadoorie Biobank.
The clinical chemistry laboratory (led by Dr Michael Hill) at CTSU (co-director Prof Collins), serving multiple epidemiological cohorts at the University of Oxford, is in the process of setting up the quantitative serum NMR metabolomics platform; it is expected to be operational by the end of 2014.
The Oxford Biobank investigations focus on research into common diseases like diabetes, obesity and cardiovascular disease – almost 5,000 serum samples have already been analysed in our lab in Finland using the serum NMR metabolomics platform.
The China Kadoorie Biobank (CKB) was set up to investigate the main genetic and environmental causes of common chronic diseases in the Chinese population. During 2004-8, more than 510,000 middle-aged adults were recruited from 10 geographically defined regions of China, with extensive data collection by questionnaire and physical measurements, and with long-term storage of blood samples for future study. All the participants are now being closely monitored for death and other health-related outcomes through linkage with established registries and health insurance databases in the study areas. Every few years, periodic re-surveys are conducted in about 25,000 surviving participants, with a repeat interview, physical measurements and blood collection (as in the baseline survey) to help assess changes in risk exposures in the study population. This large, well-established, study will be a uniquely powerful and rich resource for investigating the main causes of many common chronic diseases over the next few decades, and the information generated will advance our understanding of disease aetiology not only in China but also in other countries. Importantly, a large collection of plasma samples is already placed in Oxford. A systems epidemiology collaboration has already been agreed to study haemorrhagic stroke, which is well-characterised in the CKB. This will be the first well-powered study of haemorrhagic stroke. Genetic, metabolic and biochemical data will be analysed together with data prospectively collected at the baseline survey by questionnaire and by physical examination to enable a comprehensive investigation of the genetic and nongenetic causes, and any possible interactions, of haemorrhagic stroke.
The Estonian Biobank is a population-based biobank of the Estonian Genome Center at the University of Tartu led by Prof Metspalu. The idea is to include phenotype and genotype data of the Estonian population, with the objective of carrying out scientific research, genetic and health studies, in order to find the genes that influence the development of common diseases. Currently ~5% of the population has been studied (n>51,000) and GW as well as plasma metabolomics data collected for >10,000 individuals. Estonians represent 83%, Russians 14%, and other nationalities 3% of all participants. We have a preliminary plan to do plasma metabolomics for all the samples in the EGP (pending funding for 35,000 samples), including thousands of follow-up samples currently being collected. The EGP forms an exceptional nationwide population-based collection for systems epidemiology and the GW and serum metabolomics data eventually becoming available for >50,000 individuals (at all ages 18-) will be globally unique and also provide an excellent replication data for the Finnish cohorts.
Academy Prof Raitakari is coordinating the Cardiovascular Risk in Young Finns Study (YFS) and the the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP).
YFS is one of the largest follow-up studies into cardiovascular risk from childhood to adulthood. The main aim of the YFS is to determine the contribution made by childhood lifestyle, biological and psychological measures to the risk of cardiovascular diseases in adulthood. In 1980, over 3,500 children and adolescents all around Finland participated in the baseline study. Thereafter these subjects have been followed with several examinations, mainly 3-y intervals, including comprehensive risk factor assessments. Serum NMR metabolomics data for ~2,200 individuals are available for the 3 latest time points, 2001, 2007 and 2011 (genome-wide data also available). At all these times ultrasound examinations (e.g., cIMT) were performed to study early structural and functional atherosclerotic vascular changes.
The main purpose of the STRIP Project is the prevention of atherosclerosis and coronary heart disease by a life-style intervention, which began in infancy and has continued through puberty and early adulthood. The project was launched in 1990 when 1,062 7-month-old children and their families were enrolled. Half of the families have received individualized dietary and other life-style counselling at least twice a year whereas the rest of the families have served as a control group. The STRIP Project intervention continued until the participants reached the age of 20 years.
In the late 1970’es Finnish men had the highest cardiovascular mortality in the world. A large prospective study, The Cardiovascular Risk in Young Finns Study, was launched to elucidate the risk factors of cardiovascular diseases and their determinants in children and adolescents. Cross-sectional studies have been carried out every third year in the 1980’s. Follow-up studies in 2001 and 2007 with more than 2,000 participants included measurement of carotid intima-media thickness and arterial stiffness. These measures are indicative of subclinical atherosclerosis and established markers for future cardiovascular events. Serum NMR spectroscopy has been measured for 2200 individuals at two time points. Metabolic profiling of young healthy adults will add to increase the understanding of the mechanisms of atherosclerosis already in young adults. This allows for characterizing exposures and risk factors before the clinical manifestations of cardiovascular disease occurs. The population-based study design minimizes the influence of spurious confounding factors often present in case-control studies. In addition, the low number of individuals on medical treatment enables genuine assessment of the association of systemic metabolites with cardiovascular risk factors.
Academy Prof Laakso’s key research interests are cardiovascular complications of type 2 diabetes and the genetics of type 2 diabetes and insulin resistance.
He is leading the Metabolic Syndrome in Men (METSIM) study, which is an ongoing population-based cross-sectional study focusing on the development and metabolic characteristics of the metabolic syndrome and type 2 diabetes. Subjects, aged from 45 to 70 years, were randomly selected from the population register of the town of Kuopio in Eastern Finland (population 95,000). Every participant had a 1-day outpatient visit to the Clinical Research Unit, including an interview on the history of previous diseases and current drug treatment and an evaluation of glucose tolerance, cardiovascular risk factors as well as an extensive pattern of other demographic and clinical data. A follow-up study is ongoing. Serum NMR metabolomics data for ~10,500 individuals at the baseline are available.
Prof Salomaa is the PI for the national FINRISK studies. The cardiovascular risk factors survey, FINRISK’97, has 7,610 individuals (age 47±13y) with population risk factor monitoring with 15-y registry data for incident CHD and stroke, 30 biomarkers and 600k GW-data (n~1,500). The ‘97 collection got Academy of Finland funding for serum metabolomics in 2011 and the data came available in August 2012. The FINRISK cohorts with existing and constantly updated nation-wide registry-based follow-up for CHD and stroke, mortality and prescription drug-use provide a unique opportunity for testing of risk scores in an unbiased population setting. We aim to utilise the uniqueness of the multiomics data in these Finnish cohorts to identify high-risk population subgroups for intervention and translating emerging novel genomic and metabolic data into clinical use.
Prof Duncker is an expert in experimental cardiology and his research focuses on studying the physiology of the heart and the circulation, the aetiology and pathophysiology of cardiovascular diseases, as well as the development of new therapies for cardiovascular diseases. His research is integrated and multidisciplinary in character. Prof Duncker is a world-leading expert in experimental animal models related to isolated heart preparations and vascular preparations and is leading a large research program related to swine models in the studies of ischemic heart disease, myocardial infarction and heart failure with a view to clinical application in diagnosis and treatment.
We have started collaboration with Prof Duncker in order to set up a serum NMR metabolomics platform for swine.
Prof Mäkinen, an Associate Professor in the School of Molecular and Biomedical Science at the University of Adelaide, is an expert in developing statistical approaches to understand complex human phenotypes and diseases. As a leader of Molar (Molecular Life Course Research Group) Prof Mäkinen is investigating the connections between the diabetic kidney and vascular end-points, the role of lysosomes in the development of atherosclerosis, and the gene regulation networks that underpin the risk for coronary artery disease. The work of the research group combines exploratory computational analyses of public omics-resources with additional genomic signatures from animal experiments, and the validation of these observations in longitudinal human cohorts and follow-up time-series experiments. Prof Mäkinen has published several key findings in the field, particularly related to type 1 diabetes and metabolic phenotyping of diabetic nephropathy.
We collaborate actively with Prof Mäkinen and his team in the area of metabolic diseases and multi-omics research.