Urinary metabolic phenotyping of diet-cardiovascular disease risk associations: the OmniHeart feeding trial

Lead Research Organisation: University of Kent
Department Name: Medway School of Pharmacy

Abstract

A diet rich in complex carbohydrates from fruit/vegetables, grain/legumes, nuts/seeds, reduced in sugar, saturated fat, total fat, cholesterol and sodium (the DASH diet), has been shown to prevent and reduce high blood pressure. However, we do not completely understand which aspects of the diet are beneficial, or the biological mechanisms of its effects on high blood pressure. This has limited our ability to prevent and treat high blood pressure and its complications, which include heart disease and stroke. OmniHeart was a large (159 people) controlled feeding study, in which each participant consumed three different healthy diets (each for six weeks) with different proportion of carbohydrate, protein or unsaturated fat. Blood pressure, serum cholesterol and weight were measured during and after each dietary period, and associations of each diet with those factors were assessed. Urine specimens were also collected. The current proposal is to analyse the stored urine specimens using state-of-the art biochemical methods to obtain a metabolic fingerprint specific to each individual at each dietary period. These fingerprints, together with other clinical measurements, are to be analysed using mathematical models to identify urinary metabolites relate to the three OmniHeart diets and their effects on blood pressure and other clinical measurements. Individuals? responses to dietary interventions are to be compared to their metabolite patterns in order to identify markers that predict individual responses to the diet. This may enable doctors in the future to recommend the best specific eating pattern for each of their patients, producing maximum benefit in the reduction in blood pressure and other major risk factors.
This proposal has the potential to improve the health of individuals and populations by advancing our understanding of how diet influences blood pressure and other major heart disease risk factors. These findings could lead to new recommendations for individuals, and enhanced future public healthy policy.

Technical Summary

Cardiovascular diseases (CVD) contribute to half of the total chronic disease deaths worldwide. The global burden of CVD remains high despite established prevention/control measures for cardiovascular risk factors, such as evidence-based dietary (e.g. DASH diet) and pharmacologic recommendations for adverse blood pressure (BP) treatment. Urgent efforts are needed to advance understanding of the dietary components/metabolic pathways that underly the beneficial effects on BP, and serum lipids of DASH-type diets (i.e. diets rich in complex carbohydrates from fruit/vegetables, grain/legumes, nuts/seeds, reduced in sugar, saturated fat, total fat, cholesterol and sodium intake). This proposal aims to improve understanding of diet-disease risk associations via metabolic phenotyping of the stored urine specimens from a controlled feeding study with a randomised, 3-period crossover design comparing three interventions based on the DASH diet, each intervention with varying amounts of carbohydrate, protein or unsaturated fat, the OmniHeart Trial (N=159). Identification of diet-related urinary phenotypes from OmniHeart and urinary biomarkers for BP/other CVD risk factors will be achieved by integration of the dietary data from OmniHeart with the 1H-NMR analysed urinary metabolite data using multivariate data analysis techniques. In addition, inter-individual differences in metabolic phenotypes and responses to the three dietary interventions are to be explored, in an effort to detect factors potentially explaining inter-individual differences in CVD risk factor responses to the dietary interventions. Targeted biochemical characterisation and quantitation of candidate urinary biomarkers are to be undertaken, and associations of biomarker excretion and BP levels are to be assessed to advance our understanding of the aetiopathogenesis of adverse BP.
The proposed study have unique potential to yield new insights into metabolic pathways underlying diet-CVD risk factor associations at the population and individual level. Its results may identify potential therapeutic targets that may inform future public health policy.

Publications

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Chan Q (2017) Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview. in Hypertension research : official journal of the Japanese Society of Hypertension

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Everett JR (2013) Pharmacometabonomics and personalized medicine. in Annals of clinical biochemistry

 
Description Faculty of Science Research Fund 2014/15
Amount £2,500 (GBP)
Organisation University of Kent 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 04/2015
 
Description Kent 50th anniversary scholarship scheme
Amount £53,000 (GBP)
Organisation University of Kent 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description R01
Amount £142,800 (GBP)
Funding ID R01HL135486 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 02/2017 
End 01/2021
 
Description Vice Chancellor's PhD Scholarship
Amount £53,000 (GBP)
Organisation University of Greenwich 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2015
 
Title ASCLAN 
Description We have developed a novel data analysis strategy to for variable selection in the metabolic profiling studies. This work has been recently submitted to the Analytical Chemistry. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Paper currently under review. 
 
Title Global profiling by LC-MS 
Description The UPLC-MS equipment in the University has been used for 'traditional' chemistry work. However, we have applied and validated a global profiling method using this equipment. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact This provides global profiling facilites by MS in this region. 
 
Title SHOCSY 
Description We have developed a novel data analysis strategy to reduce the variation in the dataset and thus generate a reliable multivariate model statistics and enhance robust biomarkers selection. These are very important aspects of 'omics' studies. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact This data analysis technique may be applied to other spectroscopic data and other 'omics' type of data. We recently published this work in Analytical Chemistry. The data analysis algorithm is freely available in the public domain. 
URL http://www.msp.ac.uk/about/staff/clinical-professional/loo_ruey-leng_shocsy.html
 
Title Targetted AA analysis 
Description We have developed a targetted analysis for 20 amino acids by LC-MS. This method is faster than standard method, where it typically requires about 90 mins per sample. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact We have developed a new high throughput quantitative analysis of amino acids using HILIC UPLC-MS. This method was validated and fulfilled the FDA requirement of analytical and biologic methods. This paper has been recently published in Amino Acids 
 
Title ASCLAN 
Description ASCLAN is a clustering approach which aims to reliably distinguish discriminatory metabolites from non-discriminatory metabolites within metabonomic datasets that contains two biological classes. 
Type Of Material Data analysis technique 
Year Produced 2016 
Provided To Others? Yes  
Impact I have requests to access the data analysis algorithm which we have directed the users to the URL below 
URL http://www.msp.ac.uk/about/staff/clinical-professional/loo_ruey-leng_asclan.html
 
Title SHOCSY 
Description The Statistical HOmogeneous Cluster SpectroscopY (SHOCSY) is a new data analysis approach that was developed by our group. The SHOCSY is intended for analysing NMR metabonomics datasets but it is particularly useful when the dataset shows high variation within the group. This method enable us to identify individuals showing homogenous responses and those showing indifferent responses. 
Type Of Material Computer model/algorithm 
Year Produced 2014 
Provided To Others? Yes  
Impact Request for using the SHOCSY received from researcher. This algorithm is now freely available to download from the website within our research group. 
URL http://www.msp.ac.uk/about/staff/clinical-professional/loo_ruey-leng_shocsy.html
 
Description Air pollution 
Organisation McGill University
Department Department of Epidemiology, Biostatistics and Occupational Health
Country Canada 
Sector Academic/University 
PI Contribution Applying metabolic phenotyping to exposure studies which investigate the impact of biofuel cooking stove versus modern gaseous stoves
Collaborator Contribution McGill University provide expertise in exposure science, conducting intervention studies and biological specimens for metabolomics analysis
Impact This is multi-disciplinary collaboration involving exposure scientist, metabolomics, and epidemiologists in investing air pollutions.
Start Year 2018
 
Description Bioscience 
Organisation University of Kent
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input in metabolic profiling; Data processing and analysis on metabolic profiling based studies
Collaborator Contribution Access to spectrometer
Impact Jointly supervised a MD student. This started in Oct 2014
Start Year 2014
 
Description Childhood obesity 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Provide expertise in metabolic phenoytping, analysis of samples
Collaborator Contribution Sweden - provide expertise in bioinformatics Italy - provide expertise in clinical nutritional, samples
Impact This is an initial collaboration. We are applying for funding together at the moment.
Start Year 2017
 
Description Childhood obesity 
Organisation University of Pavia
Country Italy 
Sector Academic/University 
PI Contribution Provide expertise in metabolic phenoytping, analysis of samples
Collaborator Contribution Sweden - provide expertise in bioinformatics Italy - provide expertise in clinical nutritional, samples
Impact This is an initial collaboration. We are applying for funding together at the moment.
Start Year 2017
 
Description Darren Valley 
Organisation Dartford and Gravesham NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input into the research; Provide access for NMR to generate urinary metabolic profiling
Collaborator Contribution Access to patients group; Clinical Input
Impact We have a MD student recruiting recurrent kidney stone patients and control.
Start Year 2014
 
Description East Kent NHS 
Organisation East Kent Hospitals University NHS Foundation Trust
Department Renal Services East Kent Hospitals University
Country United Kingdom 
Sector Public 
PI Contribution Acquired NMR urine profiles; Acquired UPLC-MS urine profiles; Data analysis; Intellectual input
Collaborator Contribution Access to specimens; Access to patient information
Impact MD student registered and started this work in Sept 2013
Start Year 2013
 
Description MMRG 
Organisation University of Greenwich
Department School of Science Greenwich
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing software facilities; Sharing data analysis methods; Intellectual input
Collaborator Contribution Access and training on equipment (NMR, UPLC-SYNAPT-MS) .
Impact Secured funding for a PhD studentshiop Joint publication (23888060) In 2014, we successfully developed and validated a new method for high throughput quantitative analysis of amino acids in urine sample. We have submitted a method paper to Journal of Chromatography B.
Start Year 2011
 
Description Nutritional study 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Acquired and analysed samples from a study; Intellectual input
Collaborator Contribution Provided samples and intellectual input
Impact Joint publication (Pubmed ID 22952656 ). Submitted an abstract to annual Metabolomics conference in 2012. Abstract was selected for oral presentation at the conference. In 2014:Abstracts submitted to 1) Metabolomic Conference and 2) American Heart Association Annual Conference. Abstract was selected for poster presentation for Metabolomic Conference (2 posters) and American Heart Association Annual Conference (one poster).
Start Year 2011
 
Description OAB 
Organisation East Kent Hospitals University NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Metabolic profiling; Data analysis
Collaborator Contribution Access to unique group of patient (clinial data and samples)
Impact Started data collection for a study. Currently we have collected the data for about 50 patients with OAB. We also recruited different group of patients e.g. UTI patients.
Start Year 2013
 
Description Pharmacy practice 
Organisation University of Kent
Department Medway School of Pharmacy
Country United Kingdom 
Sector Hospitals 
PI Contribution Intellectual input; Data collection; Data analysis
Collaborator Contribution Questionnaire desgin
Impact An oral and a poster presentation at the annual Royal Pharmaceutical Society annual conference (2013). Both abstracts have been published in International Journal of Pharmacy Practice Supplement. Submitted an abstract to the Health Services Research & Pharmacy Practice Conference 2015. Two papers published in 2016
Start Year 2012
 
Description Plant (Apple) storage 
Organisation University of Greenwich
Country United Kingdom 
Sector Academic/University 
PI Contribution Provide expertise on the application of metabolomics on plant. As a secondary PhD supervisor on this aspects.
Collaborator Contribution Expertise in apple storage
Impact Currently at the early stage.
Start Year 2017
 
Description Renal group 
Organisation East Kent Hospitals University NHS Foundation Trust
Department Renal Services East Kent Hospitals University
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input in the metabonomics
Collaborator Contribution Intellectual input in the renal physiology
Impact Secured funding for PhD scholarship (Kent 50th anniversary scholarship scheme). Student presented a poster at the Experimental Biology 2013 and abstract publised in FASEB journal
Start Year 2012
 
Description Sport Science Kent 
Organisation University of Kent
Department School of Sport & Exercise Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input, instrument facility
Collaborator Contribution PhD studentship, intellectual input
Impact PhD studentship will start in Feb/Mar 2016.
Start Year 2016
 
Description glomerulas disease in mouse model 
Organisation University of Kent
Department Durrell Institute of Conservation and Ecology
Country United Kingdom 
Sector Academic/University 
PI Contribution provide metabolic phenotyping expertise
Collaborator Contribution samples from mouse model
Impact Collaboration in discussion about a potential project (assessing the urinary profile of mouse with glomerular disease)
Start Year 2017
 
Title ASCLAN 
Description ASCLAN is a clustering approach which aims to reliably distinguish discriminatory metabolites from non-discriminatory metabolites within metabonomic datasets that contains two biological classes. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact Request from users for accessing the algorithm. They have been referred to the URL below 
URL http://www.msp.ac.uk/about/staff/clinical-professional/loo_ruey-leng_asclan.html
 
Title SHOCSY 
Description The Statistical HOmogeneous Cluster SpectroscopY (SHOCSY) is a new data analysis approach that was developed by our group. The SHOCSY is intended for analysing NMR metabonomics datasets but it is particularly useful when the dataset shows high variation within the group. 
Type Of Technology Software 
Year Produced 2014 
Open Source License? Yes  
Impact Request from researchers to access the data analysis algorithm 
URL http://www.msp.ac.uk/about/staff/clinical-professional/loo_ruey-leng_shocsy.html
 
Description Aurora 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Approximately 180 female academics (predominantly universities from South East region) took part in the first day of the traininig day. The first training day was held in ILEC centre, 7th Nov. Four more training days will be held over the next few months. Other training days in different (Scotland, Manchester and Bristol) will also be held over the next few months.

Activities will be carried out atdifferrent universities to promote female leader within higher education
Year(s) Of Engagement Activity 2013
URL http://www.lfhe.ac.uk/en/programmes-events/you/aurora/
 
Description Data Analysis workshop (Pretoria, South Africa) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Postgraduate students, post doctoral researcher and professors (approximately 30 participants in total) attended the 4 days workshop on data analysis. The SHOCSY algorithm which we have developed were also introduced to the audience and have sparked interest in using the data analysis techniques
Year(s) Of Engagement Activity 2015
URL http://www.acgt.co.za/simca-metabolomics-data-analysis-workshop-is-hosted-in-gauteng.php
 
Description IMU workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact This is a metabonomics workshop organised by International Medical University (IMU), Malaysia, . The workshop was held in IMU and Puncak Alam (Campus of University Teknoglogy MARA), from 12th to 14th September 2012. I was invited to chair 2 of the sessions. The objectives of this workshop were to introduce Malaysia research community to metabonomic approaches and to highlight practical issues in conducting such research. Approximately 30 researchers registered to this workshop

1)To promote interest in my research field.
2)Attendees were keen to apply metabonomic approaches to their research.
Year(s) Of Engagement Activity 2012
 
Description Kent partnership event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Approximately 200 delegates attended the event. Delegates were predominately health care professionals but also included researchers and research students. The title of my presentation: from clinical pharmacy to personalised healthcare. This event was held in Medway on the 28th June 2012, as part of the Athena Swan session.

1) Met researchers and healthcare professionals from different fields.
2) Promoted the involvement of women in science.
Year(s) Of Engagement Activity 2012
 
Description Kent renal group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact This meeting was mainly attended by nephrologists and biochemistry analysts in Kent area. Title of presentation: Can Biomarkers Discovery and Metabonomics Help in Understanding Cardiovascular and Renal Diseases?

1) Generate interest in metabonomics among the participants
2) Successful joint application for a PhD scholarship.
Year(s) Of Engagement Activity 2012
 
Description MALA summer school 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The Mature Adults Learning Association (MALA) is a Western Australian organisation intended to provide opportunities for people to expand and enrich their knowledge in a friendly, social environment. It is for those who recognise that learning is a lifelong process, desire to keep their minds active and would like to find some practical ways to do so. I was invited to give a 2 hours presentation at the MALA annual summer school. The title of the talk Personalised Nutrition and Health; and described plans to position Western Australia as the global leader of precision medicine with the launch of the Australian National Phenome Centre, based at Murdoch University and how the general public can be involved in science. Overall, the the presentation created hugh enthusiasm and the MALA summer school was a great success with an average of more than 60 people attending my lecture. The evaluation response forms from over 75% of the attendees which were collected by MALA organiser showed that each lecture was attended by >60 participants and theycame from a wide range of places as well as locally within the Western Australia.
Year(s) Of Engagement Activity 2019
URL https://www.communitynews.com.au/mandurah-coastal-times/news/wa-scientist-of-the-year-2018-peter-new...
 
Description Research meeting in Perth 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is a one week research meeting organised by the Western Australia Health Translational Networks, together with its partners, University of Murdoch. This one week event include a meeting with a wide range of audience from the Minister of health to the charity bodies.
Year(s) Of Engagement Activity 2018
 
Description University Visit (Northwestern Univerisity) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Presentation of the results from OmniHeart Study and discussion of possible collaboration by applying metabolic phenotyping on the available datasets
Year(s) Of Engagement Activity 2016
 
Description Visit to Medical School, University of Pisa 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This meeting involves researchers and clinicians from a number of European countries. This includes Italy (University of Pavia, University of Pisa, Ebris Foundation and University of Cagliari), UK (University of Kent), Greece (University of Athens), and Belgium (ECERI). We also have three researchers calling in via video conference call from the USA. This meeting is to discuss the influence of microbiome and obesity and reviewing current evidence. Following from this meeting, the team intend to set up a consortium to investigate the topic. This is currently in the discussion process.
Year(s) Of Engagement Activity 2017