Background: Non-communicable diseases (NCDs), including diabetes and obesity, are serious global health concerns. India, impacted by rapid urbanization, has seen a shift in dietary habits and physical activity (PA) patterns, contributing to the rise of “diabesity” (the coexistence of diabetes and obesity). The evolving food environment—with a surge in processed foods and fast-food outlets—and limited spaces for PA have discouraged active healthy lifestyles, placing a strain on healthcare resources. Objective: This study examined the association of food and PA environments with diabesity among adults in urban Chennai. Materials and Methods: This cross-sectional study included 1138 adults across two electoral wards in Chennai, selected using multistage sampling. Diabesity prevalence was assessed using anthropometric (e.g., body mass index (BMI) and waist circumference) and biochemical (e.g., fasting plasma glucose, HbA1, or current use of diabetes medication) measurements; environmental influences were assessed using the Retail Food Environment Index (RFEI) and proximity to spaces for PA. Reduced rank regression (RRR) was used to identify lifestyle-environment patterns. Results: Diabesity prevalence was 32.5%, with higher rates observed among females, older adults, and physically inactive individuals. Multivariable analysis confirmed age, RFEI, and distance to space for PA as independent risk factor while PA was protective. RRR revealed two patterns, with “Passive Lifestyle and Unfavorable Environment” showing the highest diabesity risk. Conclusion: The findings highlight the need for urban planning and public health strategies to promote healthier food environments and increased PA opportunities to mitigate the burden of diabesity in urban Chennai.

BACKGROUND:In the aftermath of the Covid19 pandemic and lockdowns, there has been a growing population awaiting transthoracic echocardiograms for potential valvular heart disease. Conducting comprehensive echocardiograms for all individuals may no longer be practical, leading to substantial delays in obtaining the necessary scans. This paper explores an alternative approach, suggesting the consideration of dedicated and shorter scans specifically for patients suspected of having valvular heart disease. HYPOTHESIS:To address the increasing waiting times and improve heart valve disease detection, the British Heart Valve Society recommends a tiered approach to echocardiograms. METHODS:This approach includes basic/level 1, focused, minimum standard, and disease-specific scans. Urgency recommendations vary, with individuals experiencing exertional chest pain or pre-syncope requiring prompt scanning within 2 weeks, ideally at a valve clinic. RESULTS:Patients without known valve disease but with a murmur and stable breathlessness should be scanned as soon as possible, within a maximum of 6 weeks, balancing local demand and capacity. For those with an asymptomatic murmur and no prior scan, a basic/level 1 study is recommended to triage the necessity for a minimum standard study. Emphasizing appropriate triage for all requests, the statement guides decisions on the necessity for echocardiography, urgency level, and the required scan type. CONCLUSION:This practical Consensus Statement from the British Heart Valve Society aims to support appropriate shorter transthoracic echocardiography for patients referred for suspected valvular heart disease. The goal is to enhance capacity in a secure manner, thereby minimizing the risks associated with delays in obtaining timely scans.

Sebaceous free fatty acids are metabolized by multiple skin microbes into bioactive lipid mediators termed oxylipins. This study investigated correlations between skin oxylipins and microbes on the superficial skin of pre-pubescent children (N = 36) and adults (N = 100), including pre- (N = 25) and post-menopausal females (N = 25). Lipidomics and metagenomics revealed that Malassezia restricta positively correlated with the oxylipin 9,10-DiHOME on adult skin and negatively correlated with its precursor, 9,10-EpOME, on pre-pubescent skin. Co-culturing Malassezia with keratinocytes demonstrated a link between 9,10-DiHOME and pro-inflammatory cytokines IL-1β and IL-6 production. We also observed strong correlations between other skin oxylipins and microbial taxa, highlighting life stage differences in sebum production and microbial community composition. Our findings imply a complex host-microbe communication system mediated by lipid metabolism occurring on human skin, warranting further research into its role in skin health and disease and paving the way towards novel therapeutic targets and treatments.

The rising prevalence of diabetes, particularly in low- and middle-income countries, highlights an urgent need for innovative approaches to prevention. India faces a growing burden of type 2 diabetes (T2D), placing considerable strain on affected individuals and healthcare systems. This study aims to evaluate the effectiveness of a digital intervention designed to prevent T2D in individuals with pre-diabetes in India. A total of 3,240 individuals with pre-diabetes will be recruited across urban and rural settings in Tamil Nadu and Delhi. Participants will be cluster randomised to either the digital intervention group or the control group (usual standard of care). Clusters will comprise of wards in urban areas and villages in rural areas. Initial screening will be conducted using the Indian Diabetes Risk Score (IDRS) ≥ 30 and/or a random capillary blood glucose level ≥ 110 mg/dL. Final recruitment into the study will be based on capillary oral glucose tolerance testing (OGTT) and/or HbA1c levels. The primary outcome is incidence of T2D at 24 months, and secondary outcomes are cardiometabolic events, lifestyle and behavioural factors, and cost effectiveness of digital interventions. The study is registered with the Central Trials Registry of India (CTRI/2022/02/040650). This protocol paper details the comprehensive study design aimed at evaluating the effectiveness of a digital intervention to prevent T2D in India. If effective, the study will provide important insights into the use of technology in resource-constrained settings and offer a scalable solution for diabetes prevention. The findings could also inform future interventions and policies aimed at curbing the rising burden of diabetes in low- and middle-income countries. CTRI/2022/02/040650 (registration date: 28.02.2022). https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NjE2NzE= Enc= userName=

INTRODUCTION:mHealth technology has the potential to deliver personalized health care; however, data on cardiometabolic risk factors are limited. This study aims to assess the effectiveness of mobile health applications (apps) on cardiometabolic risk factor reduction in adults aged 25 to 60 years in urban and rural India. METHODS:The study design was a pilot randomized controlled trial conducted in Tamil Nadu, India. Smartphone users (25-60 years) with basic literacy and at high risk of developing diabetes (Indian Diabetes Risk Score ≥30 and/or fasting blood sugar [FBS] 100-125 mg/dL) were recruited. Four mobile apps (two commercially available, two novel) for cardiometabolic risk reduction were evaluated. Primary outcome (weight loss) was analyzed using intention-to-treat analysis with post hoc analysis and logistic regression models adjusted for confounders. RESULTS:A total of 5264 participants were screened, and 610 were recruited into the study. Participants (7%) dropped out largely due to the COVID-19 pandemic. Data from 567 participants were used for the final analysis. In the intention-to-treat analysis, a significant reduction in body weight was observed in the intervention group as compared with control, more so in the urban (-2.40 kg, 95% confidence interval [CI] = [-3.10, -1.69], P < .001) compared with rural population (-1.19 kg, 95% CI = [-1.55, -0.82], P < .001). Intervention group participants showed significant reductions in body mass index, waist circumference, blood pressure, FBS, total serum cholesterol, and a positive effect on dietary and physical activity behaviors compared with controls. CONCLUSIONS:mHealth interventions can reduce diabetes risk, improve cardiometabolic health, and improve lifestyle behaviors in South Asian populations. TRIAL REGISTRATION:The trial is registered with the Central Trials Registry, India (CTRI/2020/03/024327).

Asian people are under-represented in population-based, clinical, and genomic research. To address this gap, we have initiated the Health for Life in Singapore (HELIOS) longitudinal cohort study, comprising comprehensive behavioural, phenotypic, and genomic measurements from 10,004 Asian men and women of Chinese, Indian or Malay background. Phenotyping has been carried out using validated approaches, that are internationally interoperable. Health record linkage enriches both baseline phenotyping and evaluation of prospective outcomes. The integrated multi-omics data include whole-genome and RNA sequencing, quantification of DNA methylation, and metabolomic profiling. Our data reveal extensive lifestyle, physiological, genomic, and molecular diversity between the distinct Asian ethnic groups, and the biological interconnectivity between functional layers. This includes characterisation of divergent patterns of genome regulation between Asian individuals, that correlate with differences in educational attainment, dietary quality, and adiposity, and which overlap transcription factors and DNA methylation sites linked to the development of diabetes and other chronic diseases. Our unique HELIOS Asian Precision Medicine cohort study represents a state-of-the-art platform to enable biomedical researchers to understand the aetiology and pathogenesis of diverse disease outcomes in Asia, and to generate insights that have the potential to improve health outcomes for Asian populations globally. With rich, multi-layered baseline data and long-term follow-up through linkage, the HELIOS Study provides a resource to investigate the behavioural, environmental, genomic, and molecular factors impacting health in Asian populations.

Background Arterial stiffness (AS) measured by pulse wave velocity (PWV) is a well-recognized marker for increased cardiovascular disease risk in Asian and Western individuals. We evaluated factors in relation to AS using the exposure-wide association study (EWAS) approach within the Health for Life in Singapore (HELIOS) study. Subsequently, two-sample Mendelian randomization (MR) analysis was utilized to examine potential causal associations between identified factors and AS. Methods The HELIOS study is a multi-ethnic prospective cohort study that included adults aged 30-85 years. We analyzed 8,880 subjects of Chinese, Malay, and South Asian ethnicity participating in the HELIOS cohort. PWV was measured by Vicorder. We assessed 54 predictor variables using EWAS approach and correction for multiple comparisons was applied using the false discovery rate (FDR?<?5%) method. Linear regression models were used to assess the association of each predictor variable with PWV. Inverse-variance-weighted MR method was used to estimate causal effects. Results Of the 54 variables, 41 variables were significantly associated with PWV at FDR <5%. We found age, systolic blood pressure (SBP), diastolic blood pressure, and anthropometric, and body composition measurements were positively associated with PWV. Furthermore, insulin, glycated hemoglobin (HbA1c), glucose, triglycerides, albumin, alanine transaminase, gamma-glutamyl transferase, C-reactive protein, and uric acid were positively associated with PWV. Inverse associations were observed for PWV with high-density lipoprotein cholesterol (HDL-C), potassium, vitamin D, bilirubin, handgrip strength and educational level. These associations appear stronger among Chinese participants than among Malay and South Asian participants. In MR analyses, genetically predicted SBP was positively with AS, while genetically predicted HDL-C and HbA1c were inversely associated with AS. Conclusions Our systematic evaluation provides new knowledge on the complex array of anthropometric, body composition, physiological, biochemical, behavioral, and sociodemographic correlates of PWV. Our MR analysis indicates a potential causal association between SBP, HDL-C, HbA1c and AS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The HELIOS study was supported by the Singapore Ministry of Health (MOH) National Medical Research Council (NMRC) Large Collaborative Grant funding (MOH-000271), Singapore Translational Research (STaR) funding scheme (NMRC/StaR/0028/2017), National Precision Medicine Programme (Research Platform and Data Enablers; NMRC/PRECISE/2020) and intramural funding from Nanyang Technological University, Lee Kong Chain School of Medicine and the National Healthcare Group. ### 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: Nanyang Technological University Institutional Review Board (IRB-2016-11-030) 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 Requests for access to the HELIOS study data should be submitted to helios_science{at}ntu.edu.sg

Exploring the molecular correlates of metabolic health measures may identify the shared and unique biological processes and pathways that they track. Here, we performed epigenome-wide association studies (EWASs) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio (WHR), and blood-based measures of glucose, high-density lipoprotein (HDL) cholesterol, and total cholesterol. We considered blood-based DNA methylation (DNAm) from >750,000 CpG sites in over 17,000 volunteers from the Generation Scotland (GS) cohort. Linear regression analyses identified between 304 and 11,815 significant CpGs per trait at P<3.6×10-8, with 37 significant CpG sites across all six traits. Further, we performed a Bayesian EWAS that jointly models all CpGs simultaneously and conditionally on each other, as opposed to the marginal linear regression analyses. This identified between 3 and 27 CpGs with a posterior inclusion probability ≥ 0.95 across the six traits. Next, we used elastic net penalised regression to train epigenetic scores (EpiScores) of each trait in GS, which were then tested in the Lothian Birth Cohort 1936 (LBC1936; European ancestry) and Health for Life in Singapore (HELIOS; Indian-, Malay- and Chinese-ancestries). A maximum of 27.1% of the variance in BMI was explained by the BMI EpiScore in the subset of Malay-ancestry Singaporeans. Four metabolic EpiScores were associated with general cognitive function in LBC1936 in models adjusted for vascular risk factors (Standardised βrange: 0.08 - 0.12, PFDR < 0.05). EpiScores of metabolic health are applicable across ancestries and can reflect differences in brain health.

Nigericin, an ionophore derived from Streptomyces hygroscopicus , is arguably the most commonly used tool compound to study the NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates the NLRP1 inflammasome in human keratinocytes. In this study, we resolve the mechanistic basis of nigericin-driven NLRP1 inflammasome activation. In multiple nonhematopoietic cell types, nigericin rapidly and specifically inhibits the elongation stage of the ribosome cycle by depleting cytosolic potassium ions. This activates the ribotoxic stress response (RSR) sensor kinase ZAKα, p38, and JNK, as well as the hyperphosphorylation of the NLRP1 linker domain. As a result, nigericin-induced pyroptosis in human keratinocytes is blocked by extracellular potassium supplementation, ZAKα knockout, or pharmacologic inhibitors of ZAKα and p38 kinase activities. By surveying a panel of ionophores, we show that electroneutrality of ion movement is essential to activate ZAKα-driven RSR and a greater extent of K+ depletion is necessary to activate ZAKα-NLRP1 than NLRP3. These findings resolve the mechanism by which nigericin activates NLRP1 in nonhematopoietic cell types and demonstrate an unexpected connection between RSR, perturbations of potassium ion flux, and innate immunity.

India grapples with a formidable health challenge, with an estimated 315 million adults afflicted with hypertension and 100 million living with diabetes mellitus. Alarming statistics reveal rates for poor treatment and control of hypertension and diabetes. In response to these pressing needs, the Community Control of Hypertension and Diabetes (CoCo-HD) program aims to implement structured lifestyle interventions at scale in the southern Indian states of Kerala and Tamil Nadu. This research is designed to evaluate the implementation outcomes of peer support programs and community mobilisation strategies in overcoming barriers and maximising enablers for effective diabetes and hypertension prevention and control. Furthermore, it will identify contextual factors that influence intervention scalability and it will also evaluate the program’s value and return on investment through economic evaluation. The CoCo-HD program is underpinned by a longstanding collaborative effort, engaging stakeholders to co-design comprehensive solutions that will be scalable in the two states. This entails equipping community health workers with tailored training and fostering community engagement, with a primary focus on leveraging peer supportat scale in these communities. The evaluation will undertake a hybrid type III trial in, Kerala and Tamil Nadu states, guided by the Institute for Health Improvement framework. The evaluation framework is underpinned by the application of three frameworks, RE-AIM, Normalisation Process Theory, and the Consolidated Framework for Implementation Research. Evaluation metrics include clinical outcomes: diabetes and hypertension control rates, as well as behavioural, physical, and biochemical measurements and treatment adherence. The anticipated outcomes of this study hold immense promise, offering important learnings into effective scaling up of lifestyle interventions for hypertension and diabetes control in low- and middle-income countries (LMICs). By identifying effective implementation strategies and contextual determinants, this research has the potential to lead to important changes in healthcare delivery systems. The project will provide valuable evidence for the scaling-up of structured lifestyle interventions within the healthcare systems of Kerala and Tamil Nadu, thus facilitating their future adaptation to diverse settings in India and other LMICs.

Understanding how changes in individual food preferences in a dynamic environment translate into dietary choices helps to unravel the aetiology of suboptimal nutrition in the population. To facilitate the measurements of food preferences in a multiethnic Asian population, we aimed to develop and validate the Macronutrient and Taste Preference Ranking Task (MTPRT) in an Asian population. We shortlisted 1770 local food items based on the predominant macronutrient groups (≥50 % macronutrient content is protein or fat or carbohydrates), classified their taste clusters, standard-photographed a final list of 36 food items, and developed an electronic survey through cognitive interviews with 30 participants. We then validated the MTPRT amongst 66 participants (mean (SD) age = 47.4 (11.7) years, 57.6 % male, with Chinese: Malay: Indian ethnicity ratio 3:1:1), through random crossover administration of sweet and savoury standard meals with equivalent macronutrients across 2 study visits over a week. The average duration taken to complete MTPRT was 14.1 (5.3) minutes. The sweet and savoury taste preference scores were inversely correlated (r = -0.9, p < 0.0001). The liking and preference for savoury taste were reduced after consuming savoury meals (p = 0.0009). The intra-person correlations for MTPRT scores were all r > 0.6, p < 0.001. The macronutrient preference scores were all positively associated with the self-reported macronutrient intakes derived from the Food Frequency Questionnaire, independent of sex, age, ethnicity, and BMI. Our study demonstrates the validity and reproducibility of MTPRT in multiethnic Asian populations for future evaluation of food preferences in multiethnic Asian population.

The burden of cardiovascular disease (CVD) is rising in the Asia-Pacific region, in contrast to falling CVD mortality rates in Europe and North America. To provide new insights into the pathways influencing cardiovascular risk in Asian populations, we quantified 883 metabolites by untargeted mass spectroscopy in 8,124 Singaporean adults, and investigated their relationships to carotid intima media thickness (cIMT), a marker of atherosclerosis. We found that plasma concentrations of 3beta-hydroxy-5-cholestenoate (3BH5C), a cholesterol metabolite, associated inversely with cIMT (Beta[SE]=-0.013[0.002]). Genetic instruments support a causal relationship of 3BH5C metabolic pathways on cardiovascular risk, with a 5-6 fold higher effect size in Asians (ORGSMR[95% CI]=0.89[0.87-0.92], ORIVW[95% CI]=0.86[0.80-0.92]) compared to Europeans (ORIVW[95% CI] = 0.98[0.96-0.99]). Colocalization analyses indicate the presence of a shared causal variant between 3BH5C plasma levels and expression of ferredoxin-1 (FDX1), a protein essential for sterol and bile acid synthesis. We validated FDX1 as a key regulator of 3BH5C synthesis in hepatocytes, and macrophages, and cholesterol efflux in aortic smooth muscle cells, through knockout and overexpression models. In summary, this study makes an important contribution to our understanding of the metabolic basis for atherosclerosis in Asian populations, and identifies FDX1 as a potential therapeutic target for prevention of CVD.

Background: A large number of epidemiologic studies across the world indicate a growing link between obesity and diabetes. The metropolitan city of Chennai in South India is experiencing an alarming increase in diabetes and obesity. Aim: The aim of this study was to determine the prevalence of and risk factors for diabetes and obesity together termed as “diabesity” among adults in urban Chennai. Materials and Methods: This was a community-based cross-sectional door-to-door study done as part of a large National Institute of Health and Care Research (NIHR)––a funded project aimed to understand patterns and determinants of health in South Asia. Of the 200 wards in Chennai, 34 wards were surveyed in the main project and two wards were selected randomly for this substudy. Five community enumeration blocks were selected using a systematic sampling technique. Participants aged ≥18 years were selected using a consecutive sampling method. Results: Of the 1138 participants studied, the prevalence of diabesity was found to be 34.3%(n = 390). Of the study participants, 74.8% had obesity (61.9%––generalized obesity; 68.5%––abdominal obesity) and 43.0% had diabetes. As age increased, the diabesity risk also increased gradually from 30 to 39 years (odds ratio [OR]: 3.6[95%, confidence interval [CI]: 1.4–8.9]) to 50–59 years (OR: 5.4[95%, CI: 2.2–13.2]), whereas there was a slight decrease in risk after 60 years (OR: 5.1[95%, CI: 2.1–12.3]). Females had nearly twice the risk of diabesity compared to men (OR: 1.8, P < 0.001), and physically inactive individuals had 1.7 times increased risk (P < 0.001). Conclusion: We report in this study that the prevalence of the dual metabolic defect (diabesity) is alarmingly high in urban Chennai. This study was an attempt to understand the epidemiology of diabesity.

Background Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. Objectives We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. Methods We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort ( n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. Results Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144–0.298) increase in TEWL ( P = 2.82E–08), a 0.336% (95%CI: 0.148–0.524) decrease in skin moisture ( P = 4.66E–04) and a 0.184% (95%CI: 0.144–0.224) decrease in pH ( P = 1.36E–19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189–0.520 and Beta –0.170; 95%CI: –0.253 to –0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI’s possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. Conclusion We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention.

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 StatementKari E Wong, Patricia A Sheridan, Rangaprasad Sarangarajan and Gregory A Michelotti are employees of Metabolon. The other authors declare no competing financial interests.### Funding StatementWe 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 DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe 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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesRequest to access the data is available via helios_science@ntu.edu.sg for consideration of HELIOS study principal investigators.

Precision medicine promises to transform healthcare for groups and individuals through early disease detection, refining diagnoses and tailoring treatments. Analysis of large-scale genomic–phenotypic databases is a critical enabler of precision medicine. Although Asia is home to 60% of the world’s population, many Asian ancestries are under-represented in existing databases, leading to missed opportunities for new discoveries, particularly for diseases most relevant for these populations. The Singapore National Precision Medicine initiative is a whole-of-government 10-year initiative aiming to generate precision medicine data of up to one million individuals, integrating genomic, lifestyle, health, social and environmental data. Beyond technologies, routine adoption of precision medicine in clinical practice requires social, ethical, legal and regulatory barriers to be addressed. Identifying driver use cases in which precision medicine results in standardized changes to clinical workflows or improvements in population health, coupled with health economic analysis to demonstrate value-based healthcare, is a vital prerequisite for responsible health system adoption.

BACKGROUND Polygenic risk scores (PRS), commonly referred to as genetic or genomic risk scores, aggregate the effects of multiple genetic variants into a single composite estimate of genetic risk. PRS scores are typically used to predict the risk of developing a disease or to explain the phenotypic variation, and are derived from the effect sizes observed in large-scale genome-wide association studies (GWAS). Unlike rare monogenic diseases such as cystic fibrosis, which are attributable to genetic variants in single genes, with large effects on disease status, common complex diseases such as type 2 diabetes mellitus (T2DM) are polygenic, with risk contributed by a panel of genetic variants present throughout the genome. The concept of integrating information from these multiple genetic variants into a single metric of genetic risk was initially proposed in the shape of genetic risk scores, which generally limited the score to include single-nucleotide polymorphisms (SNPs) that were common and reached genome-wide significance in the initial GWASs. In contrast, PRS incorporates information from a much larger set of genetic variants, typically hundreds of thousands, including SNPs below the threshold for genome-wide statistical significance, and often with much more modest effect sizes.[1] Indeed, recent findings have pointed to how polygenic background could also increase the accuracy of risk estimation for individuals with monogenic risk variant in conditions such as familial hypercholesterolaemia, hereditary breast and ovarian cancer, and Lynch syndrome.[2] DEVELOPMENT IN PRS APPROACHES Initial PRS approaches were constructed using linear or logistic regression models to quantify individual SNP effect sizes. However, recent work has demonstrated that in the presence of linkage disequilibrium (LD), prediction accuracy of the commonly used approach of LD pruning/clumping followed by P value thresholding is inadequate.[3] More recent PRS approaches have used shrinkage and Bayesian methods such as lassosum, LDpred and PRS-CS.[3,4,5] In particular, Khera et al.[6] demonstrated that by taking a genome-wide PRS approach with LDpred, they were able to identify 1.5%–8.0% of the population at greater than three-fold increased risk of five common diseases, including coronary artery disease (CAD), atrial fibrillation, T2DM, inflammatory bowel disease and breast cancer. This was especially striking for CAD, where the observed prevalence of 8% is 20-fold higher than that of the carrier frequency of rare monogenic mutations conferring comparable risk. Indeed, these PRS provide predictive utility independently and additively to conventional clinical risk scores.[7,8] Having a high PRS contributed 21%–38% higher lifetime risk and 4–9 years earlier disease onset compared to an average PRS across common diseases. In fact, 13% of early-onset coronary heart disease cases were predicted only with the addition of PRS in the assessment model.[7] Work in UK Biobank also demonstrated in parallel that inclusion of PRS, in addition to traditional risk factors, increased approximately 7% in the number of events prevented.[8] ROLE OF ETHNICITY IN PRS Recent evidence has demonstrated the importance of using ethnic-appropriate PRS in disease risk prediction. Martin et al.[9] showed that PRS based on European-derived summary statistics had substantially lower accuracy when applied to non-European populations across 17 anthropometric and blood panel traits; accuracy was 1.6–4.5-fold lower on average in Hispanic/Latino Americans, South Asians, East Asians and Africans, compared to Europeans. This is corroborated by our own data (under review), in which we show that PRS for T2DM prediction in South Asians are significantly more accurate when based on South Asian rather than European association test results. These observations are particularly relevant to Asian populations such as Singapore, where we are strongly dependent on European-derived summary statistics for PRS, given that almost 80% of all current GWAS participants are of European ancestry.[9] The limited availability of genomic data for Asian populations underpins the current national effort in performing whole genome sequencing in a cohort of 100,000 individuals (SG100K) as part of Singapore’s National Precision Medicine programme. This will allow us to assess the impact of combining an individual’s PRS, lifestyle information and clinical information on chronic disease risk prediction and the associated implementation of early intervention, through lifestyle modification and/or early pharmacological intervention. Given the multi-ethnic make-up of the Singapore population, these population-specific PRS will prove invaluable in applying PRS to the greatest benefit in Singapore. CHALLENGES AND THE FUTURE OF PRS UTILITY Despite the potential benefits that clinical usage of PRS may bring, there remain many challenges and critical considerations in the journey to implementation. One concern is the quality control surrounding PRS generation, and where it should sit compared to typical clinical genetic testing, which is performed in Clinical Laboratory Improvement Amendments (CLIA)-certified (or equivalent) laboratories and includes genetic counselling sessions. It is therefore essential to ensure education and training of healthcare professionals, as well as the general public, in the interpretation and understanding of these novel scores. Funding mechanisms should be in place to establish who should be responsible for the cost of genotyping and PRS generation, how best to handle any incidental findings, and whether PRS could be shared between primary health institutions and private practitioners. Public trust must be built, as PRS could be perceived by some as discriminating or stigmatising, and there may be concerns about its impact on one’s insurance policies. There are also concerns around equal utility, and efforts such as SG100K, which aim to increase the genetic diversity of participants in GWAS, will help to improve utility for all groups, especially for underrepresented Asian communities. To ensure long-term successful implementation of PRS in routine clinical care, it is critical to demonstrate health and economic benefits. Public health and economic benefits will differ greatly depending on the actual use case for PRS, and considering possible clinical actions such as cost of intervention and screening strategies.[10] A significant health economics benefit could be achieved by the generation of multiple concurrent PRS for multiple diseases based on a single genotyping, and leveraging on the panel to optimise treatment and screening strategies across endpoints. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Valvular regurgitation represents an important cause of cardiovascular morbidity and mortality. Imaging is pivotal in the evaluation of native valve regurgitation and echocardiography is the primary imaging modality for this purpose. The imaging assessment of valvular regurgitation should integrate quantification of the regurgitation, assessment of the valve anatomy and function, and the consequences of valvular disease on cardiac chambers. In clinical practice, the management of patients with valvular regurgitation largely relies on the results of imaging. It is crucial to provide standards that aim at establishing a baseline list of measurements to be performed when assessing native valve regurgitation. The present document aims to present clinical guidance for the multi-modality imaging assessment of native valvular regurgitation.