BACKGROUND:Health inequities arising from systemic factors and contextual conditions result in avoidable and unjust differences in health outcomes, with profound social and economic implications. Health inequities can frequently go unreported in observational studies. Observational studies can uniquely inform how we understand and address persisting health inequities through collecting, reporting and analyzing health equity factors using 'inclusive' methodological considerations. While the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) reporting guideline aims to improve observational study reporting quality, existing extensions lacked a specific focus on health equity. Engaging those who will use or be impacted by research ("knowledge users"), including participant-research collaborators, is central to bridging the gap between knowledge production and real-world application. Therefore, the purpose of this study was to gather a range of perspectives from these knowledge users as part of, and to inform, the development of the STROBE-Equity guideline extension, which aims to improve the reporting of equity-relevant considerations in observational studies. METHODS:This study used a qualitative description approach, employing semi-structured key informant interviews and framework analysis to collect and analyze the views of researchers, policymakers, decision-makers, funders, journal editors, ethicists, and participant-research collaborators. Participants were purposefully sampled to reflect diverse perspectives from knowledge users with relevant experience on health equity reporting. RESULTS:Eleven key informants participated in the interviews. Information from interviews was categorized into seven themes: "Clarifying equity", "Equity is dynamic", "The challenges of making equity claims", "Making reporting on equity feasible", "Using reporting guidelines to manage tension", "Potential for better outcomes", and "Nobody's perspective is neutral". Participants emphasized the need for standardized equity-relevant reporting practices and offered insight into challenges, opportunities, and strategies for integrating equity-relevant considerations into observational study reporting. CONCLUSIONS:Findings show that participants viewed equity as a complex concept and stressed the need for practical guidance to support equity reporting in observational studies. They highlighted barriers such as limited time, resources, and publication word limits, and perceived the STROBE-Equity extension as a valuable tool for structuring reporting, raising awareness, and encouraging reflection, with the potential to improve the quality and impact of equity-relevant research.

The effect of dietary intake on body weight may vary based on individual genetic differences. However, children are rarely used in such investigations. The aim was to identify possible genetic moderation through polygenic scores (PGS) for BMI, of the association between dietary intakes and BMI in children. The study sample included children who were part of a French-Canadian birth-cohort study. BMI data was available on seven occasions between ages 4 and 13 years. FFQ (juice and fruit drinks, sweets and snack foods, meats, and fruits and vegetables) and 24-h dietary recall (proteins, lipids, carbohydrates, total energy) data were available up to 4 years. Linear mixed models were used to account for repeated BMI measurements. The consumption of juice and fruit drinks (in girls), sweets and snack foods, fruits and vegetables, proteins, lipids, carbohydrates and total energy were associated with BMI. Associations with BMI increased with age (kg/m2 per year) for fruits and vegetables (β: -0.03, 95%CI: -0.06;-0.01), lipids (β: 0.11, 95%CI: 0.01;0.22), carbohydrates (β: 0.05, 95%CI: 0.01;0.08), and total energy (β: 0.07, 95%CI: 0.02;0.12), and with higher values of a PGS (kg/m2 per SD) for proteins (β: 0.54, 95%CI: 0.03;1.06), lipids (β: 0.63, 95%CI: 0.12;1.13), and total energy (β: 0.32, 95%CI: 0.06;0.58). Using longitudinal data, we showed that the associations between specific dietary intakes and BMI may vary depending on age and genetic susceptibility in childhood.

BackgroundCholine is an essential nutrient involved in human health and development across the lifespan. The evidence on choline and its health effects has been growing; yet the findings are inconsistent.AimWe aimed to map the current evidence and identify gaps in knowledge.MethodsWe conducted a scoping review of the studies that examined relationships between choline exposure and any health outcomes. MEDLINE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched for research involving humans and published between January 2000 and May 2025. Screening and data abstraction were performed in duplicate.ResultsA total of 117 primary studies were included. Most of the studies were conducted in North America (54%) and Europe (22%). Cardiometabolic disease accounted for the largest proportion (34%), followed by offspring neurodevelopment (19%) and liver conditions (12%). The studies were predominantly observational (prospective 60%, retrospective 12%, cross-sectional 20%). The evidence regarding potential benefits and harms was reported to be insufficient or equivocal for many health outcomes. Based largely on data from small randomized controlled trials in women with prenatal exposure to alcohol or infants with fetal alcohol syndrome disorder, high maternal choline intake/status was associated with improved neurocognition and neurodevelopmental outcomes in the offspring.ConclusionPotential benefits of high maternal choline intake/status was indicated for neurodevelopment of the offspring; however, the evidence was insufficient or equivocal for most of the outcomes reviewed. A more comprehensive synthesis incorporating preclinical evidence from animal studies will improve the current understanding of choline and its health effects.

BACKGROUND:Vitamin D, which is essential for calcium and phosphorus homeostasis, may also influence immune regulation and offer protection against preterm birth (PTB). Per- and polyfluoroalkyl substances (PFAS) are associated with both increases and decreases in 25-hydroxyvitamin D (25OHD) concentrations and have been shown to compete for binding sites on the vitamin D receptor (VDR). We investigated associations between PFAS and preterm birth, and the potential modification by vitamin D status and single nucleotide polymorphisms (SNPs) of the VDR. METHODS:We used adjusted discrete-time survival models for individual PFAS, and quantile g-computation for the PFAS mixture. Effect modification was investigated (additive and multiplicative) by first-trimester vitamin D status (≥vs. < 50 nmol/L 25OHD) and four VDR variants: ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236) and FokI (rs2228570). RESULTS:Among 1857 singleton births, 114 (6%) were PTBs. Each doubling of perfluorononanoic acid (PFNA) was associated with an approximate 30% increase in the odds of PTB. We found significant qualitative interactions between a number of PFAS and vitamin D status, with elevated risk specific to those with sufficent vitamin D status (≥50 nmol/L) for PFNA (OR = 1.56, 95% CI:1.15, 2.12). We observed effect modification of the association between PFNA and PFDA by some VDR genotypes. The stratified analysis showed elevated odds among genotypes of ApaI (Aa, OR = 1.78, 95% CI: 1.19, 2.60), BsmI (BB, OR = 1.75, 95% CI: 1.13, 2.64), and TaqI (TT, OR = 1.73, 95% CI: 1.13, 2.59) with each doubling in PFNA. Perfluorodecanoic acid (PFDA) was associated with an increased odds of PTB among those homozygous for the major alleles of BsmI (OR BB = 1.76, 95% CI: 1.17, 2.58) and TaqI (ORTT = 1.65, 95% CI: 1.13, 2.38). CONCLUSIONS:PFNA exposure was associated with elevated odds of PTB, with evidence of modification by vitamin D status and VDR genotype. PFAS may disrupt receptor-mediated pathways, producing pleiotropic effects. We postulate the observed modification by vitamin D status is partly due to confounding by fish consumption. Further investigation into these associations in other pregnancy cohorts is warranted.

Background:Cardiovascular and metabolic diseases account for an increasing share of morbidity and mortality globally. Folic acid supplementation has been linked to a lowered risk of stroke and some metabolic indicators due to its involvement in homocysteine and one-carbon metabolism and its role in the production of nitric oxide; however, the evidence on these associations is inconclusive. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (dietary intake, supplementation, or blood concentrations) with any cardiometabolic outcome. We performed screening, data abstraction, and risk of bias assessment in duplicate, and assessed the credibility of the evidence using predefined criteria. Results:We identified 113 unique associations from 49 reviews. The included syntheses mostly had low risk of bias of and provided pooled risk estimates from intervention trials or prospective cohorts. A larger volume of evidence was available for composite cardiovascular outcomes, coronary heart disease, and stroke compared to other outcomes. No association reached a convincing or highly suggestive level of credibility. Six directional associations and five null associations met the criteria for a suggestive level of credibility. Three dose-response relationships, all at suggestive levels of credibility, supported an association between higher dietary folate intake and a reduced risk of coronary heart disease and stroke. Conclusion:The available evidence on the association between folate status and cardiometabolic outcomes primarily focuses on secondary prevention of cardiometabolic diseases and substantially underrepresents low- and middle-income countries. More large-scale studies are warranted to validate a relationship between folate status and cardiometabolic events or indicators. Overall, the evidence landscape around folate and cardiometabolic diseases appears to be limited both in volume and scope. Registration:PROSPERO: CRD42021265041.

Background:Folate has been examined extensively in relation to carcinogenesis due to its role in one-carbon metabolism impacting the synthesis of DNA and RNA, methylation processes, and genomic integrity. Current evidence on the relationship between folate status and the risk of cancer is equivocal: low or deficient folate status may contribute to an increased risk of cancers, while high-dose folic acid supplementation may have adverse effects on carcinogenesis. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects up to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (measured as dietary intake, supplementation, or blood concentrations) with any specific cancer outcome. Screening, data extraction, and risk of bias assessment were performed in duplicate. We assessed the credibility of the evidence using predefined criteria. Results:We found 67 syntheses, of which 57 provided meta-analyses. Over half of the syntheses had a high risk of bias. We identified 168 unique associations (unique exposure - unique outcome - unique setting) across 10 cancer types, 3 system cancers, and total cancer. Of these, we assessed 15 directional associations (colorectal, oesophageal, and total cancers) to be at a highly suggestive level of credibility, and 17 directional and 10 null associations to be at a suggestive level of credibility. Conclusions:The available evidence for each category of unique association was generally limited. Highly suggestive associations were found for oesophageal, colorectal, childhood brain and spinal tumours and total cancers. More robust primary studies are warranted to follow-up the signal of a positive relationship reported for prostate cancer warranting further research. Evidence was weak for all but colorectal and oesophageal cancers, or the central nervous system cancers in children. Registration:PROSPERO: CRD42021265041.

Background:Folate is essential for normal growth and in human health throughout the lifecycle. Clinical deficiency of folate impairs DNA synthesis and results in megaloblastic anaemia, while suboptimal folate status before and in early pregnancy results in an elevated risk of neural tube defects (NTD). The evidence on the association of folate status with other health outcomes is largely fragmented and understudied. We conducted a series of umbrella reviews examining the association between folate and multiple health outcomes in various populations and settings. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and DARE from inception to February 2024 for systematic reviews with or without meta-analyses examining an association between folate intake/status and any health outcome. We performed screening and data extraction in duplicate and assessed the risk of bias using the ROBIS tool. Evidence was then characterised into unique associations (unique exposure measure - unique outcome measure - unique setting). For each category of unique associations, we identified the evidence based on the statistical power, recency of publication and the potential risk of bias. All unique associations were evaluated for credibility using predefined criteria. Results:We retrieved 3565 records and included 283 in the final synthesis. The evidence on anaemia consisted of four intervention trials demonstrating effectiveness of folic acid supplementation during pregnancy in reducing the risk of megaloblastic anaemia (relative risk (RR) = 0.21; 95% CI = 0.11, 0.38; I2 = 15%). Maternal folic acid use was also significantly inversely related to the prevention of NTD at birth (RR = 0.31; 95% CI = 0.16, 0.60; I2 = 0%) and NTD recurrence (RR = 0.30; 95% CI = 0.14, 0.65; I2 = 0%). This relationship was supported by the inverse association reported between low maternal blood folate concentrations and the increased risk of NTD. Further evidence showed that fortification of food with folic acid was associated with the lower prevalence of NTD on a population-level. Conclusion:In NTDs and anaemia, we identified strong evidence supporting the protective role of folate status based on intervention trials and observational studies. More recent reviews examining the role of folate in other less well understood health conditions will be presented in the subsequent reports. Registration:PROSPERO: CRD42021265041.

Background Autoimmune diseases and bone density loss (osteopenia and osteoporosis) are chronic conditions of complex aetiology that affect diverse populations. Folate may be associated with a higher risk of these disorders due to its essential role in one-carbon metabolism required for nucleotide synthesis, homocysteine metabolism, and methylation processes. However, the evidence on this association is inconclusive. Methods We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure (dietary intake, supplementation, or blood concentrations) and any autoimmune diseases or skeletal outcomes. Pairs of researchers screened the retrieved syntheses, extracted the relevant data, assessed their risk of bias using the ROBIS tool, and evaluated the credibility of the evidence using predefined criteria. Results We found 19 reviews reporting 25 unique associations: 15 on autoimmune diseases (multiple sclerosis, inflammatory bowel disease, psoriasis, human immunodeficiency virus, vitiligo, and systemic lupus erythematosus) and 10 on skeletal outcomes (fractures and bone mineral density loss). Most of the syntheses consisted of small-scale case-control studies. The risk of bias in the included syntheses was high. Owing to the small sample sizes, all the unique associations were assessed to be at a weak level of credibility. Conclusions The evidence on the relationship between folate status and autoimmune diseases or skeletal outcomes was limited in breadth and depth. Most of the 25 unique associations were reported by a single synthesis comprising small-scale studies. Subgroup analyses or dose-response analyses were severely limited or unavailable. More well-powered, prospective studies investigating the relationships between folate and autoimmune and skeletal conditions are warranted. Registration PROSPERO: CRD42021265041.

Metabolomic epidemiology has expanded rapidly, but publications often lack sufficient detail for readers to assess study design, analytical methods, sources of bias, and the robustness and reproducibility of findings. Existing reporting recommendations in epidemiology and metabolomics do not fully address the specific challenges that arise when these fields are combined. To improve the completeness and transparency of reporting, we developed the Strengthening the Reporting of Metabolomic Epidemiology (STROBE-MetEpi) statement, an extension of the original STROBE guidance for observational research. The STROBE-MetEpi checklist includes 31 items and subitems covering the Title, Abstract, Introduction, Methods, Results, Discussion, and Other Information sections of metabolomic epidemiology studies. This explanation and elaboration document is intended to complement the STROBE-MetEpi statement by explaining the rationale for each checklist item and providing published examples of transparent reporting. It applies to studies using metabolomic profiling to explore human health, but not to randomized trials, methodological studies, reviews, or multi-omics studies. As with previous STROBE explanation and elaboration documents, its purpose is to improve how studies are reported, not to prescribe how they should be conducted. The STROBE-MetEpi statement and this accompanying document should support authors, reviewers, editors, and readers in improving the reporting, appraisal, interpretation, and reproducibility of metabolomic epidemiology research.

Background:The global burden of neuropsychiatric disorders has been increasing rapidly. Folate has been studied in the context of these disorders due to its role in cellular methylation capacity, which is crucial for normal neuronal gene expression and neurotransmitter syntheses. Epidemiological evidence linking folate and neuropsychiatric disorders is growing, yet inconclusive. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure and any neuropsychiatric disorders. Two independent reviewers screened the syntheses in two stages and extracted relevant data. Evidence was categorised into unique associations (unique exposure measure - unique outcome - unique setting). We identified evidence for each category of unique associations. We evaluated the risk of bias of all included syntheses using ROBIS and assessed the credibility of evidence using predefined criteria. Results:From a total of 76 syntheses, we identified 44 unique associations from meta-analyses and 18 unique associations from qualitative syntheses across 14 outcome categories. Most of the reviews consisted of case-control studies or cross-sectional studies, and most were at high risk of bias. We identified two associations at a suggestive level of credibility: folic acid supplementation during or before pregnancy was associated with a reduced risk of perinatal depression, while prenatal maternal folic acid use was associated with a reduced risk of autism spectrum disorder in offspring. Seven associations were downgraded to weak due to unavailable data. Other associations were at a weak level of credibility due to insufficient statistical power. Conclusions:The available evidence on the relationship between folate status and neuropsychiatric disorders primarily comprised data from observational studies, limiting causal inference on folate exposure and the risk of onset or progression of neuropsychiatric disorders. Prospective studies and sex-stratified analyses could add to the evolving knowledge on this topic. Registration:PROSPERO: CRD42021265041.

Importance Observational studies can provide valuable insights to inform decisions on health equity. Existing guidelines for reporting such studies, such as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, currently lack specific considerations for reporting on health equity. Health equity is defined as the absence of avoidable and unfair differences that may exist across individuals and populations due to structural and systematic inequities in living and working conditions, opportunities, and resources. To address this gap, the research team developed an extension of the STROBE statement (STROBE-Equity) that focuses on reporting health equity data and considerations. Observations This consensus statement followed steps for developing a consensus- and evidence-based guideline using an integrated knowledge translation approach to ensure engagement of knowledge users from diverse disciplines and perspectives. Selection criteria for the research team and steering committees prioritized diversity across age, gender, and geography. The STROBE checklist was extended to include 10 items specifically aimed at reporting health equity considerations. To develop these items, the research team drew on evidence from empirical studies including a scoping review of the literature, methodological review, key informant interviews, an online survey, and a global consensus meeting of experts. For each of the 10 equity-related items, the statement provides an explanation and example(s) of transparent reporting practices. Conclusions and Relevance Use of the STROBE-Equity extension alongside the STROBE statement when writing up completed reports of observational studies has the potential to advance the reporting of health equity data and considerations. Improved reporting of this information may help knowledge users better identify and apply evidence relevant to populations experiencing inequities.

High intraocular pressure (IOP) is an important risk factor for glaucoma, which is influenced by genetic and environmental factors. However, the etiology of high IOP remains uncertain. Metabolites are compounds involved in metabolism which provide a link between the internal (genetic) and external environments. O-methylascorbate has been reported to be associated with IOP. In addition, researchers have identified several genetic variants which are associated with metabolite concentrations, including O-methylascorbate and another vitamin C related metabolite, ascorbic acid 2-sulfate. We aimed to understand how O-methylascorbate and ascorbic acid 2-sulfate, or genetic variants associated with these metabolites, modify the associations between dietary environmental variables and IOP. We used data from 8060 participants of the Canadian Longitudinal Study on Aging. Using linear models adjusted for relevant covariates, we tested for interactions between six genetic variants previously found to be associated with O-methylascorbate and ascorbic acid 2-sulfate and four environmental variables related to diet (alcohol consumption frequency, smoking status, fruit consumption, and vegetable consumption). We also tested for interactions between serum concentrations of O-methylascorbate and ascorbic acid 2-sulfate and these environmental factors. We used a False Discovery Rate approach to correct for the 32 interaction tests performed. One interaction was suggestively significant after multiple testing correction (adjusted P-value < 0.1): rs8050812 and alcohol consumption frequency. Understanding how genetic variants and metabolites interact with the environment could shed light on biological pathways controlling IOP and lead to improved prevention and treatment of glaucoma.

By integrating findings from large-scale omics analyses with experimental tests, this study aims to decipher susceptibility genes and the underlying biological mechanisms involved in the development of colorectal cancer (CRC). We first conducted a trans-ancestry transcriptome-wide association study (TWAS) among 57,402 CRC cases and 119,110 controls, aiming to examine how altered gene expression influences CRC risk in European and Asian populations. Then, functional experiments in (i) CRC cell lines and (ii) tumor xenografts were conducted to examine potential underlying mechanisms involved in colorectal carcinogenesis. Further, a drug sensitivity test was employed to explore possible clinical implications for CRC treatment. The TWAS identified 67 genes highly associated with CRC risk, 23 of which were novel findings. Functional annotation of variants within TWAS-identified loci revealed that the majority (93.6%) showed evidence of transcriptional regulatory mechanisms via proximal promoter or distal enhancer-promoter interactions. Among the identified susceptibility genes, splicing factor 3a subunit 3 (SF3A3) may act as an oncogene on the basis that overexpression of this gene was significantly associated with increased risk of CRC (P = 5.75 × 10−11). Further cell and animal experiments confirmed that SF3A3 plays an oncogenic role in CRC development, and the underlying biological mechanism is likely to be related to its anti-apoptosis effect. The drug sensitivity test suggested that phenethyl isothiocyanate (PEITC) targeting SF3A3 can inhibit CRC progression. This study identified novel CRC susceptibility genes and potential biological mechanisms of SF3A3 involved in CRC development, providing important insight into the etiology and potential leads to the treatment of CRC.

Objective: To comprehensively evaluate the interaction between diet quality and multivitamin intake during pregnancy on offspring neurodevelopment. Methods: This analysis was grounded in mother-child dyads from the 3D Cohort Study in Quebec, Canada. Among the 2366 participants initially enrolled in the 3D study, 1535 women successfully completed the 3-day food record during 20-24 weeks of gestation. A Canadian adaptation of the Healthy Eating Index (HEI-C) 2010 was used to quantify diet quality. The total HEI-C score was dichotomized into low and high diet quality by median split. Cognitive and motor development in childhood were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Language abilities were measured using the toddler short-form version of the MacArthur-Bates Communicative Development Inventories (MCDI) questionnaire, administered in either English or French. After excluding participants with missing covariate data, cognitive, motor, and language development scores at 2 years of age were available for 1066, 1040, and 981 children, respectively. Multiple linear regression models were employed to calculate adjusted effect estimates. The interaction on an additive scale was assessed by incorporating a product term into the linear regression model. Results: Statistically significant interactions were detected between diet quality and multivitamin intake in relation to the cognitive and language development outcomes of the offspring (interaction p-values were 0.018 and 0.023, respectively). The lowest cognitive and language scores were observed in the group of women who neither took multivitamins nor maintained a high-quality diet. Among women not taking multivitamins, a high-quality diet was associated with improved offspring cognitive and language scores (mean difference [95% CI] = 4.2 [0.1, 8.2], p = 0.04; and 11.3 [3.1, 19.5], p = 0.01, respectively). However, among women taking multivitamins, no such associations were identified. Conversely, in participants with a low-quality diet, multivitamin intake was associated with a 3.0-point increase in cognitive composite scores (95% CI: 0.3, 5.8, p = 0.03), but this was not the case for those with a high-quality diet. No statistically significant interactions were observed between maternal diet quality and multivitamin intake for motor development outcomes. Conclusions: Adequate nutritional supply during pregnancy, achieved either through a high-quality diet or multivitamin supplementation, is fundamental for the neurodevelopment of children.

ABSTRACT Objective To examine whether prenatal opioid use disorder (OUD) diagnosis is associated with the risk of congenital anomalies (CAs) in offspring. Methods We conducted a population‐based study of mother–newborn dyads comprising. 4143 761 births delivered in Canada from 2006 to 2021. We used robust Poisson regression to examine the association between prenatal OUD diagnosis and risk of non‐chromosomal CAs, adjusted for maternal age, parity, multiple gestation, co‐morbidities (including mental health disorders, chronic illnesses and other substance use disorders), and infant sex. Results We identified a total of 21, 638 births to persons who were diagnosed with prenatal OUD and 65, 992 (159.3 per 10,000) newborns with CAs. The overall risk of CAs was 2.3 times higher in infants born to birthing persons with a diagnosis of OUD (95% CI 2.2, 2.5). Compared to those without OUD diagnoses, births to persons with a diagnosis of OUD had a higher risk of specific types of congenital microcephaly (aRR 5.2, 95% CI 4.1, 6.6), cleft palate (RR 4.8, 95% CI 3.7, 6.1), pulmonary valve atresia with intact ventricular septum (aRR 2.7, 95% CI 1.1, 6.7), and atrial septal defect (aRR 3.1, 95% CI 2.8, 3.5), among others. In particular, infants born to those with an OUD diagnosis had a 1.8 (95% CI 1.4, 2.3)‐fold increased risk of having severe congenital heart disease. Conclusion Our findings suggest an association between prenatal OUD diagnosis and certain CAs in the offspring. Future research is necessary to better understand the role of socio‐demographic factors on these associations.