Abstract
Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with -1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.
| Original language | English |
|---|---|
| Pages (from-to) | 2309-2320 |
| Number of pages | 12 |
| Journal | Nature Medicine |
| Volume | 28 |
| Issue number | 11 |
| Early online date | 22 Sept 2022 |
| DOIs | |
| Publication status | Published - Nov 2022 |
Bibliographical note
Funding Information:This research was conducted using data from UK Biobank, a major biomedical database ( https://www.ukbiobank.ac.uk/ ) via application no. 51157. This project was funded by Charité – Universitätsmedizin Berlin and Einstein Foundation Berlin. The study was supported by the BMBF-funded Medical Informatics Initiative (HiGHmed, nos. 01ZZ1802A–01ZZ1802Z). Resources of Flaticon.com were used in the design of the figures. M. Kivimaki received relevant founding from The Wellcome Trust (no. 221854/Z/20/Z), the Medical Research Council (no. MR/R024227/1) and the US National Institute on Aging (no. R01AG056477). E.B.v.d.A. received relevant funds from the Dutch Research Council (NWO, no. VENI: 09150161810095). The WHII study was supported by the Wellcome Trust (no. 221854/Z/20/Z), the Medical Research Council (no. MR/R024227/1) and the US National Institute on Aging (no. R01AG056477). Ethical approval for the WHII study was obtained from the University College London Hospital Committee on the Ethics of Human Research and the NHS Health Research Authority, London-Harrow Research Ethics Committee (nos. REC 85/0938 and IRAS 142374). Written informed consent from participants was obtained at each contact. The authors thank A. Ryan and M. Newbury from the DPUK platform team for their swift and immediate help with data access. The RS is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)-NL (no. 184.021.007) and JNPD under the project PERADES (grant no. 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics). The RS protocol was approved by the Medical Ethics Committee of the Erasmus MC Rotterdam, the Netherlands (no. MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport (Population Screening Act WBO, license no. 1071272-159521-PG). In accordance with the Declaration of Helsinki, the RS obtained written informed consent from all participants before their entering the study. The LLS received funding from the European Union’s Seventh Framework Program (FP7/2007-2011) under grant agreement no. 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem, no. IGE05007), the Center for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant nos. 05040202 and 050-060-810), all within the framework of the Netherlands Genomics Initiative, NWO, Unilever Colworth and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO, no. 184.021.007). The LLS protocol was approved by the Medical Ethical Committee of Leiden University Medical Center before the start of the study (no. P01.113). In accordance with the Declaration of Helsinki, the LLS obtained informed consent from all participants before their entry into the study. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant no. 2001 D 032). PROSPER was supported by the European Federation of Pharmaceutical Industries Associations (EFPIA), Innovative Medicines Initiative Joint undertaking, European Medical Information Framework (EMIF, grant no. 115372) and the European Commission under the Health Cooperation Work Program of the 7th Framework Program (grant no. 305507) ‘Heart ‘omics’ in AGEing’ (HOMAGE). The PROSPER protocol was approved by institutional ethics review boards of Cork University (Ireland), Glasgow University (UK) and Leiden University Medical Center (the Netherlands). In accordance with the Declaration of Helsinki, the PROSPER study obtained informed consent from all participants before their entry into the study.
Funding Information:
This research was conducted using data from UK Biobank, a major biomedical database (https://www.ukbiobank.ac.uk/) via application no. 51157. This project was funded by Charité – Universitätsmedizin Berlin and Einstein Foundation Berlin. The study was supported by the BMBF-funded Medical Informatics Initiative (HiGHmed, nos. 01ZZ1802A–01ZZ1802Z). Resources of Flaticon.com were used in the design of the figures. M. Kivimaki received relevant founding from The Wellcome Trust (no. 221854/Z/20/Z), the Medical Research Council (no. MR/R024227/1) and the US National Institute on Aging (no. R01AG056477). E.B.v.d.A. received relevant funds from the Dutch Research Council (NWO, no. VENI: 09150161810095). The WHII study was supported by the Wellcome Trust (no. 221854/Z/20/Z), the Medical Research Council (no. MR/R024227/1) and the US National Institute on Aging (no. R01AG056477). Ethical approval for the WHII study was obtained from the University College London Hospital Committee on the Ethics of Human Research and the NHS Health Research Authority, London-Harrow Research Ethics Committee (nos. REC 85/0938 and IRAS 142374). Written informed consent from participants was obtained at each contact. The authors thank A. Ryan and M. Newbury from the DPUK platform team for their swift and immediate help with data access. The RS is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Metabolomics measurements were funded by Biobanking and Biomolecular Resources Research Infrastructure (BBMRI)-NL (no. 184.021.007) and JNPD under the project PERADES (grant no. 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics). The RS protocol was approved by the Medical Ethics Committee of the Erasmus MC Rotterdam, the Netherlands (no. MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport (Population Screening Act WBO, license no. 1071272-159521-PG). In accordance with the Declaration of Helsinki, the RS obtained written informed consent from all participants before their entering the study. The LLS received funding from the European Union’s Seventh Framework Program (FP7/2007-2011) under grant agreement no. 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem, no. IGE05007), the Center for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant nos. 05040202 and 050-060-810), all within the framework of the Netherlands Genomics Initiative, NWO, Unilever Colworth and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO, no. 184.021.007). The LLS protocol was approved by the Medical Ethical Committee of Leiden University Medical Center before the start of the study (no. P01.113). In accordance with the Declaration of Helsinki, the LLS obtained informed consent from all participants before their entry into the study. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant no. 2001 D 032). PROSPER was supported by the European Federation of Pharmaceutical Industries Associations (EFPIA), Innovative Medicines Initiative Joint undertaking, European Medical Information Framework (EMIF, grant no. 115372) and the European Commission under the Health Cooperation Work Program of the 7th Framework Program (grant no. 305507) ‘Heart ‘omics’ in AGEing’ (HOMAGE). The PROSPER protocol was approved by institutional ethics review boards of Cork University (Ireland), Glasgow University (UK) and Leiden University Medical Center (the Netherlands). In accordance with the Declaration of Helsinki, the PROSPER study obtained informed consent from all participants before their entry into the study.
Funding Information:
U.L. received grants from Bayer, Novartis and Amgen, consulting fees from Bayer, Sanofi, Amgen, Novartis and Daichy Sankyo and honoraria from Novartis, Sanofi, Bayer, Amgen and Daichy Sankyo. J.D. received consulting fees from GENinCode UK Ltd, honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk and Bayer and is Chief Medical Advisor to Our Future Health. R.E. received honoraria from Sanofi and consulting fees from Boehringer Ingelheim. All other authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s).
