Metabolic variation reflects dietary intake in a multi-ethnic Asian population

Dietary biomarkers reflecting habitual diet are explored largely in European and American populations. However, the food metabolome is highly complex, with its composition varying to region and culture. Here, by assessing 1,055 plasma metabolites and 169 foods/beverages in 8,391 comprehensively phenotyped individuals from the multi-ethnic Asian HELIOS cohort (69% Chinese, 12% Malay, 19% South Asian), we report novel observations for ethnic-relevant and common foods. Using machine-learning feature selection approach, we developed dietary multi-biomarker panels (3-39 metabolites each) for key foods and beverages in respective training sets. These panels comprised distinct and shared metabolite networks, and captured variances in intake prediction models in test sets better than single biomarkers. Composite metabolite scores, derived from the biomarker panels, associated significantly and more strongly with clinical phenotypes (HOMA-IR, type 2 diabetes, BMI, fat mass index, carotid intima-media thickness and hypertension), compared to self-reported intakes. Lastly, in 235 individuals that returned for a repeat visit (averaged 322 days apart), diet-metabolite relationships were robust over time, with predicted intakes, derived from biomarker panels and metabolite scores, showing better reproducibility than self-reported intakes. Altogether, our findings show new insights into multi-ethnic diet-related metabolic variations and new opportunity to link exposure to health outcomes in Asian populations. ### Competing Interest Statement Kari E Wong, Patricia A Sheridan, Rangaprasad Sarangarajan and Gregory A Michelotti are employees of Metabolon. The other authors declare no competing financial interests. ### Funding Statement We express our thanks to participants of the HELIOS study and the HELIOS operation team for recruitment, organisation and data/sample collection. This study (NTU IRB: 2016-11-030) is supported by Singapore Ministry of Health (MOH) National Medical Research Council (NMRC) under its OF-LCG funding scheme (MOH-000271-00), Singapore Translational Research (StaR) funding scheme (NMRC/StaR/0028/2017), the National Research Foundation, Singapore through the Singapore MOH NMRC and the Precision Health Research, Singapore (PRECISE) under the National Precision Medicine programme and intramural funding from Nanyang Technological University, Lee Kong Chian School of Medicine and the National Healthcare Group. Dorrain Low is also supported by the National Research Foundation, Singapore, through the Singapore MOH NMRC and PRECISE under the National Precision Medicine programme. Parts of figures were created with Biorender.com. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Datasets were derived from the Health for Life in Singapore (HELIOS) study (ethics approval IRB-2016-11-030, www.healthforlife.sg), a multi-ethnic prospective cohort of adults aged 30-84 years old. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Request to access the data is available via helios_science@ntu.edu.sg for consideration of HELIOS study principal investigators.