Physical activity, metabolites, and breast cancer associations.

BACKGROUND: The effects of usual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites, and breast cancer risk. METHODS: Physical activity levels were assessed using doubly labeled water, accelerometers, and 24-hr recalls in the IDATA study (N = 707 participants, ages 50-74 years, 51% women), with 1-6 assessments over 12 months and two blood sample collections. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of metabolites with postmenopausal breast cancer in a nested case-control study (621 cases, 621 controls), all statistical tests were 2-sided. RESULTS: Physical activity was associated with 164 metabolites spanning numerous pathways, including amino acid and fatty acid metabolism. Twelve of these metabolites were also associated with breast cancer risk, ten of which supported a protective role of physical activity. Notably, higher physical activity was associated with lower 16alpha-hydroxy DHEA 3-sulfate (androgen) and adipoylcarnitine (fatty acid), both of which were associated with increased breast cancer risk (OR per 1 standard deviation (SD)=1.34, 95% CI = 1.16-1.55 and 1.26,1.11-1.42, respectively). Higher physical activity energy expenditure was also associated with lower sphingomyelin (d18:1/20:1, d18:2/20:0), which was associated with a reduced breast cancer risk (0.82,0.73-0.93). CONCLUSION: Physical activity is associated with a broad range of metabolites, many of which are consistent with a protective effect against breast cancer. Our findings highlight potential metabolic pathways for cancer prevention.

Social, behavioral and clinical risk factors are associated with clonal hematopoiesis.

BACKGROUND: Risk factors including smoking, alcohol intake, physical activity (PA), and sleep patterns have been associated with cancer risk. Clonal hematopoiesis (CH), including mosaic chromosomal alterations (mCAs) and clonal hematopoiesis of indeterminate potential (CHIP), is linked to increased hematopoietic cancer risk, and could be used as common pre-clinical intermediates for better understanding associations of risk factors with rare hematologic malignancies. METHODS: We analyzed cross-sectional data from 478,513 UK Biobank participants without hematologic malignancies using multivariable adjusted analyses to assess the associations between lifestyle factors and CH types. RESULTS: Smoking was reinforced as a potent modifiable risk factor for multiple CH types, with dose-dependent relationships persisting post-cessation. Males in socially deprived areas of England had lower risk of mosaic loss of chromosome Y (mLOY), females with moderate/high alcohol consumption (2-3 drinks/day) had increased mLOX risk (OR=1.17, 95%CI:[1.09-1.25], p=8.31×10-6) compared to light drinkers, active males (moderate-high PA) had elevated risks of mLOY (PA Category 3: OR=1.06, 95%CI:[1.03-1.08], p=7.57×10-6) and men with high BMI (≥40) had reduced risk of mLOY (OR=0.57, 95%CI:[0.51-0.65], p=3.30×10-20). Sensitivity analyses with BMI adjustment attenuated the effect in the mLOY-PA associations (IPAQ2: OR=1.03, 95%CI:[1.00-1.06], p=2.13×10-2 and IPAQ3: OR=1.03, 95%CI:[1.01-1.06], p=7.77×10-3). CONCLUSIONS: Our study reveals associations between social deprivation, smoking, alcohol consumption, and CH risk, suggesting these exposures could contribute to common types of CH and potentially rare hematologic cancers. IMPACT: This study underscores the impact of lifestyle factors on CH frequency, emphasizing social, behavioral, and clinical influences and the importance of socio-behavioral contexts when investigating CH risk factors.

Methods and participant characteristics in the Cancer Risk in Vegetarians Consortium: a cross-sectional analysis across 11 prospective studies.

BACKGROUND: The associations of vegetarian diets with risks for site-specific cancers have not been estimated reliably due to the low number of vegetarians in previous studies. Therefore, the Cancer Risk in Vegetarians Consortium was established. The aim is to describe and compare the baseline characteristics between non-vegetarian and vegetarian diet groups and between the collaborating studies. METHODS: We harmonised individual-level data from 11 prospective cohort studies from Western Europe, North America, South Asia and East Asia. Comparisons of food intakes, sociodemographic and lifestyle factors were made between diet groups and between cohorts using descriptive statistics. RESULTS: 2.3 million participants were included; 66% women and 34% men, with mean ages at recruitment of 57 (SD: 7.8) and 57 (8.6) years, respectively. There were 2.1 million meat eaters, 60,903 poultry eaters, 44,780 pescatarians, 81,165 vegetarians, and 14,167 vegans. Food intake differences between the diet groups varied across the cohorts; for example, fruit and vegetable intakes were generally higher in vegetarians than in meat eaters in all the cohorts except in China. BMI was generally lower in vegetarians, particularly vegans, except for the cohorts in India and China. In general, but with some exceptions, vegetarians were also more likely to be highly educated and physically active and less likely to smoke. In the available resurveys, stability of diet groups was high in all the cohorts except in China. CONCLUSIONS: Food intakes and lifestyle factors of both non-vegetarians and vegetarians varied markedly across the individual cohorts, which may be due to differences in both culture and socioeconomic status, as well as differences in questionnaire design. Therefore, care is needed in the interpretation of the impacts of vegetarian diets on cancer risk.

Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom.

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. Methods: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations. Results: Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases. Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Multivitamin Use and Mortality Risk in 3 Prospective US Cohorts.

Importance: One in 3 US adults uses multivitamins (MV), with a primary motivation being disease prevention. In 2022, the US Preventive Services Task Force reviewed data on MV supplementation and mortality from randomized clinical trials and found insufficient evidence for determining benefits or harms owing, in part, to limited follow-up time and external validity. Objective: To estimate the association of MV use with mortality risk, accounting for confounding by healthy lifestyle and reverse causation whereby individuals in poor health initiate MV use. Design, Setting, and Participants: This cohort study used data from 3 prospective cohort studies in the US, each with baseline MV use (assessed from 1993 to 2001), and follow-up MV use (assessed from 1998 to 2004), extended duration of follow-up up to 27 years, and extensive characterization of potential confounders. Participants were adults, without a history of cancer or other chronic diseases, who participated in National Institutes of Health-AARP Diet and Health Study (327 732 participants); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (42 732 participants); or Agricultural Health Study (19 660 participants). Data were analyzed from June 2022 to April 2024. Exposure: Self-reported MV use. Main Outcomes and Measures: The main outcome was mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. Results: Among 390 124 participants (median [IQR] age, 61.5 [56.7-66.0] years; 216 202 [55.4%] male), 164 762 deaths occurred during follow-up; 159 692 participants (40.9%) were never smokers, and 157 319 participants (40.3%) were college educated. Among daily MV users, 49.3% and 42.0% were female and college educated, compared with 39.3% and 37.9% among nonusers, respectively. In contrast, 11.0% of daily users, compared with 13.0% of nonusers, were current smokers. MV use was not associated with lower all-cause mortality risk in the first (multivariable-adjusted HR, 1.04; 95% CI, 1.02-1.07) or second (multivariable-adjusted HR, 1.04; 95% CI, 0.99-1.08) halves of follow-up. HRs were similar for major causes of death and time-varying analyses. Conclusions and Relevance: In this cohort study of US adults, MV use was not associated with a mortality benefit. Still, many US adults report using MV to maintain or improve health.

Association of tea and coffee consumption and biliary tract cancer risk: The Biliary Tract Cancers Pooling Project.

BACKGROUND AND AIMS: Tea and coffee are widely consumed beverages worldwide. We evaluated their association with biliary tract cancer (BTC) incidence. APPROACH AND RESULTS: We pooled data from 15 studies in the Biliary Tract Cancers Pooling Project to evaluate associations between tea and coffee consumption and biliary tract cancer development. We categorized participants as nondrinkers (0 cup/day), moderate drinkers (>0 and <3 cups/day), and heavy drinkers (≥3 cups/day). We estimated multivariable HRs and 95% CIs using Cox models. During 29,911,744 person-years of follow-up, 851 gallbladder, 588 intrahepatic bile duct, 753 extrahepatic bile duct, and 458 ampulla of Vater cancer cases were diagnosed. Individuals who drank tea showed a statistically significantly lower incidence rate of gallbladder cancer (GBC) relative to tea nondrinkers (HR=0.77; 95% CI, 0.64-0.91), and intrahepatic bile duct cancer (IHBDC) had an inverse association (HR=0.81; 95% CI, 0.66-1.00). However, no associations were observed for extrahepatic bile duct cancer (EHBDC) or ampulla of Vater cancer (AVC). In contrast, coffee consumption was positively associated with GBC, with a higher incidence rate for individuals consuming more coffee (HR<3 cups/day =1.29; 95% CI, 1.01-1.66; HR≥3 cups/day =1.49; 95% CI, 1.11-1.99, Ptrend=0.01) relative to coffee nondrinkers. However, there was no association between coffee consumption and GBC when restricted to coffee drinkers. There was little evidence of associations between coffee consumption and other biliary tract cancers. CONCLUSIONS: Tea consumption was associated with a lower incidence of GBC and possibly IHBDC. Further research is warranted to replicate the observed positive association between coffee and GBC.

White Blood Cell Count, Neutrophil-to-Lymphocyte Ratio, and Incident Cancer in the UK Biobank.

BACKGROUND: The peripheral white blood cell (WBC) and neutrophil-to-lymphocyte ratio (NLR) reflect levels of inflammation and adaptive immunity. They are associated with cancer prognosis, but their associations with cancer incidence are not established. METHODS: We evaluated 443,540 cancer-free adults in the UK Biobank with data on total WBC and its subsets, follow-up starting one year after baseline. Cox regression was used to estimate hazard ratios (HR) per quartile of WBC or NLR for incidence of 73 cancer types. RESULTS: 22,747 incident cancers were diagnosed during a median of 6.9 years of follow-up. WBC was associated with risk of cancer overall [HR, 1.05; 95% confidence interval (CI), 1.03-1.06], chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL, 2.79; 95% CI, 2.45-3.18), lung cancer (1.14, 95% CI, 1.08-1.20), and breast cancer (95% CI, 1.05-1.02-1.08). NLR was positively associated with cancer overall (HR, 1.03; 95% CI, 1.02-1.04, per quartile) and kidney cancer (1.16; 95% CI, 1.07-1.25), and inversely with CLL/SLL (0.38; 95% CI, 0.33-0.42). CONCLUSIONS: High WBC or NLR may reflect excessive inflammatory status, promoting development of some cancers. Conversely, low NLR indicates a relative rise in lymphocytes, which could reflect an increase in circulating premalignant cells before CLL/SLL diagnosis. Peripheral WBC and NLR, in combination with other clinical information or biomarkers, may be useful tools for cancer risk stratification. IMPACT: Elevated levels of WBCs or an increased NLR may indicate an overly active inflammatory response, potentially contributing to the eventual onset of certain types of cancer.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

BACKGROUND: Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. METHODS: Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. RESULTS: TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24-2.92; p = .003] and 1.26 [1.17-1.36; p < .0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76-0.79; p < .001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p = .0003). CONCLUSIONS: Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Measuring diet by metabolomics: a 14-d controlled feeding study of weighed food intake.

BACKGROUND: Metabolomics has the potential to enhance dietary assessment by revealing objective measures of many aspects of human food intake. Although metabolomics studies indicate that hundreds of metabolites are associated with dietary intake, correlations have been modest (e.g., r < 0.50), and few have been evaluated in controlled feeding studies. OBJECTIVES: The aim of this study was to evaluate associations between metabolites and weighed food and beverage intake in a controlled feeding study of habitual diet. METHODS: Healthy postmenopausal females from the Women's Health Initiative (N = 153) were provided with a customized 2-wk controlled diet designed to emulate their usual diet. Metabolites were measured by liquid chromatography tandem mass spectrometry in end-of-study 24-h urine and fasting serum samples (1293 urine metabolites; 1113 serum metabolites). We calculated partial Pearson correlations between these metabolites and intake of 65 food groups, beverages, and supplements during the feeding study. The threshold for significance was Bonferroni-adjusted to account for multiple testing (5.94 × 10-07 for urine metabolites; 6.91 × 10-07 for serum metabolites). RESULTS: Significant diet-metabolite correlations were identified for 23 distinct foods, beverages, and supplements (171 distinct metabolites). Among foods, strong metabolite correlations (r ≥ 0.60) were evident for citrus (highest r = 0.80), dairy (r = 0.65), and broccoli (r = 0.63). Among beverages and supplements, strong correlations were evident for coffee (r = 0.86), alcohol (r = 0.69), multivitamins (r = 0.69), and vitamin E supplements (r = 0.65). Moderate correlations (r = 0.50-0.60) were also observed for avocado, fish, garlic, grains, onion, poultry, and black tea. Correlations were specific; each metabolite correlated with one food, beverage, or supplement, except for metabolites correlated with juice or multivitamins. CONCLUSIONS: Metabolite levels had moderate to strong correlations with weighed intake of habitually consumed foods, beverages, and supplements. These findings exceed in magnitude those previously observed in population studies and exemplify the strong potential of metabolomics to contribute to nutrition research. The Women's Health Initiative is registered at clinicaltrials.gov as NCT00000611.

The Time-Dependent Association Between Irritable Bowel Syndrome and All-Cause and Cause-Specific Mortality: A Prospective Cohort Study Within the UK Biobank.

INTRODUCTION: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, but few studies have evaluated mortality risks among individuals with IBS. We explored the association between IBS and all-cause and cause-specific mortality in the UK Biobank. METHODS: We included 502,369 participants from the UK Biobank with mortality data through 2022. IBS was defined using baseline self-report and linkage to primary care or hospital admission data. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality using multivariable Cox proportional hazards regression models within partitioned follow-up time categories (0-5, >5-10, and >10 years). RESULTS: A total of 25,697 participants (5.1%) had a history of IBS at baseline. After a median follow-up of 13.7 years, a total of 44,499 deaths occurred. Having an IBS diagnosis was strongly associated with lower risks of all-cause (HR = 0.70, 95% CI = 0.62-0.78) and all-cancer (HR = 0.69, 95% CI = 0.60-0.79) mortality in the first 5 years of follow-up. These associations were attenuated over follow-up, but even after 10 years of follow-up, associations remained inverse (all-cause: HR = 0.89, 95% CI = 0.84-0.96; all-cancer: HR = 0.87, 95% CI = 0.78-0.97) after full adjustment. Individuals with IBS had decreased risk of mortality from breast, prostate, and colorectal cancers in some of the follow-up time categories. DISCUSSION: We found that earlier during follow-up, having diagnosed IBS was associated with lower mortality risk, and the association attenuated over time. Additional studies to understand whether specific factors, such as lifestyle and healthcare access, explain the inverse association between IBS and mortality are needed.

Association of glycaemic index and glycaemic load with type 2 diabetes, cardiovascular disease, cancer, and all-cause mortality: a meta-analysis of mega cohorts of more than 100 000 participants.

BACKGROUND: There is debate over whether the glycaemic index of foods relates to chronic disease. We aimed to assess the associations between glycaemic index (GI) and glycaemic load (GL) and type 2 diabetes, cardiovascular disease, diabetes-related cancers, and all-cause mortality. METHODS: We did a meta-analysis of large cohorts (≥100 000 participants) identified from the Richard Doll Consortium. We searched the Cochrane Library, MEDLINE, PubMed, Embase, Web of Science, and Scopus for cohorts that prospectively examined associations between GI or GL and chronic disease outcomes published from database inception to Aug 4, 2023. Full-article review and extraction of summary estimates data were conducted by three independent reviewers. Primary outcomes were incident type 2 diabetes, total cardiovascular disease (including mortality), diabetes-related cancers (ie, bladder, breast, colorectal, endometrial, hepatic, pancreatic, and non-Hodgkin lymphoma), and all-cause mortality. We assessed comparisons between the lowest and highest quantiles of GI and GL, adjusting for dietary factors, and pooling their most adjusted relative risk (RR) estimates using a fixed-effects model. We also assessed associations between diets high in fibre and whole grains and the four main outcomes. The study protocol is registered with PROSPERO, CRD42023394689. FINDINGS: From ten prospective large cohorts (six from the USA, one from Europe, two from Asia, and one international), we identified a total of 48 studies reporting associations between GI or GL and the outcomes of interest: 34 (71%) on various cancers, nine (19%) on cardiovascular disease, five (10%) on type 2 diabetes, and three (6%) on all-cause mortality. Consumption of high GI foods was associated with an increased incidence of type 2 diabetes (RR 1·27 [95% CI 1·21-1·34]; p<0·0001), total cardiovascular disease (1·15 [1·11-1·19]; p<0·0001), diabetes-related cancer (1·05 [1·02-1·08]; p=0·0010), and all-cause mortality (1·08 [1·05-1·12]; p<0·0001). Similar associations were seen between high GL and diabetes (RR 1·15 [95% CI 1·09-1·21]; p<0·0001) and total cardiovascular disease (1·15 [1·10-1·20]; p<0·0001). Associations between diets high in fibre and whole grains and the four main outcomes were similar to those for low GI diets. INTERPRETATION: Dietary recommendations to reduce GI and GL could have effects on health outcomes that are similar to outcomes of recommendations to increase intake of fibre and whole grain. FUNDING: Banting and Best and the Karuna Foundation.

Associations between actigraphy-measured sleep duration, continuity, and timing with mortality in the UK Biobank.

STUDY OBJECTIVES: To examine the associations between sleep duration, continuity, timing, and mortality using actigraphy among adults. METHODS: Data were from a cohort of 88 282 adults (40-69 years) in UK Biobank that wore a wrist-worn triaxial accelerometer for 7 days. Actigraphy data were processed to generate estimates of sleep duration and other sleep characteristics including wake after sleep onset (WASO), number of 5-minute awakenings, and midpoint for sleep onset/wake-up and the least active 5 hours (L5). Data were linked to mortality outcomes with follow-up to October 31, 2021. We implemented Cox models (hazard ratio, confidence intervals [HR, 95% CI]) to quantify sleep associations with mortality. Models were adjusted for demographics, lifestyle factors, and medical conditions. RESULTS: Over an average of 6.8 years 2973 deaths occurred (1700 cancer, 586 CVD deaths). Overall sleep duration was significantly associated with risk for all-cause (p < 0.01), cancer (p < 0.01), and CVD (p = 0.03) mortality. For example, when compared to sleep durations of 7.0 hrs/d, durations of 5 hrs/d were associated with a 29% higher risk for all-cause mortality (HR: 1.29 [1.09, 1.52]). WASO and number of awakenings were not associated with mortality. Individuals with L5 early or late midpoints (<2:30 or ≥ 3:30) had a ~20% higher risk for all-cause mortality, compared to those with intermediate L5 midpoints (3:00-3:29; p ≤ 0.01; e.g. HR ≥ 3:30: 1.19 [1.07, 1.32]). CONCLUSIONS: Shorter sleep duration and both early and late sleep timing were associated with a higher mortality risk. These findings reinforce the importance of public health efforts to promote healthy sleep patterns in adults.

Multivitamin use and all-cause and cause-specific mortality in cancer survivors.

BACKGROUND: Despite no sufficient evidence on benefits and harms of multivitamin use, cancer survivors use multivitamins as a self-care strategy to improve or maintain health. We examined if multivitamin use was associated with mortality in cancer survivors. METHODS: 15,936 male and 7026 female cancer survivors in the NIH-AARP Diet and Health Study were included in the analysis. Types and frequency of multivitamin use at on average 4.6 years after cancer diagnosis were assessed. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression models. RESULTS: Multivitamin use was not associated with lower all-cause mortality risk in all female (RR = 0.94, 95% CI:0.87-1.01 daily vs. no use) or male cancer survivors (RR = 0.96, 95% CI:0.91-1.00); however, a modest inverse association for CVD mortality was observed in female survivors of reproductive cancers (RR = 0.75, 95% CI:0.61-0.92) and male survivors of non-reproductive cancers (RR = 0.81, 95% CI:0.70-0.94). Multivitamin use was also associated with a lower risk of cancer-specific mortality in survivors of skin (RR = 0.65, 95% CI:0.48-0.88) and breast (RR = 0.79, 95% CI:0.65-0.95) cancer. DISCUSSION: Multivitamin use may provide a modest survival benefit to some cancer survivors. Cancer care providers should talk with cancer survivors about potential benefits and harms of multivitamin use.

Actigraphy-derived measures of sleep and risk of prostate cancer in the UK Biobank.

BACKGROUND: Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep. METHODS: We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to <2 hours vs <1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs <1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43). CONCLUSIONS: Of the sleep characteristics studied, higher wakefulness after sleep onset-a measure of poor sleep quality-was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted.

The association between inflammatory bowel disease and all-cause and cause-specific mortality in the UK Biobank.

PURPOSE: Inflammatory bowel disease (IBD) has a rising global prevalence. However, the understanding of its impact on mortality remains inconsistent so we explored the association between IBD and all-cause and cause-specific mortality. METHODS: This study included 502,369 participants from the UK Biobank, a large, population-based, prospective cohort study with mortality data through 2022. IBD was defined by baseline self-report or from primary care or hospital admission data. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality in multivariable Cox proportional hazards regression models. RESULTS: A total of 5799 (1.2%) participants had a history of IBD at baseline. After a median follow-up of 13.7 years, 44,499 deaths occurred. Having IBD was associated with an increased risk of death from all causes (HR = 1.16, 95% CI = 1.07-1.24) and cancer (HR = 1.16, 95% CI = 1.05-1.30), particularly colorectal cancer (CRC) (HR = 1.56, 95% CI = 1.17-2.09). We observed elevated breast cancer mortality rates for individuals with Crohn's disease, and increased CRC mortality rates for individuals with ulcerative colitis. In stratified analyses of IBD and all-cause mortality, mortality risk differed by individuals' duration of IBD, age at IBD diagnosis, body mass index (BMI) (PHeterogeneity = 0.03) and smoking status (PHeterogeneity = 0.01). Positive associations between IBD and all-cause mortality were detected in individuals diagnosed with IBD for 10 years or longer, those diagnosed before the age of 50, all BMI subgroups except obese individuals, and in never or current, but not former smokers. CONCLUSIONS: We found that having IBD was associated with increased risks of mortality from all causes, all cancers, and CRC. This underscores the importance of enhanced patient management strategies and targeted prevention efforts in individuals with IBD.

Dietary biomarkers-an update on their validity and applicability in epidemiological studies.

The aim of this literature review was to identify and provide a summary update on the validity and applicability of the most promising dietary biomarkers reflecting the intake of important foods in the Western diet for application in epidemiological studies. Many dietary biomarker candidates, reflecting intake of common foods and their specific constituents, have been discovered from intervention and observational studies in humans, but few have been validated. The literature search was targeted for biomarker candidates previously reported to reflect intakes of specific food groups or components that are of major importance in health and disease. Their validity was evaluated according to 8 predefined validation criteria and adapted to epidemiological studies; we summarized the findings and listed the most promising food intake biomarkers based on the evaluation. Biomarker candidates for alcohol, cereals, coffee, dairy, fats and oils, fruits, legumes, meat, seafood, sugar, tea, and vegetables were identified. Top candidates for all categories are specific to certain foods, have defined parent compounds, and their concentrations are unaffected by nonfood determinants. The correlations of candidate dietary biomarkers with habitual food intake were moderate to strong and their reproducibility over time ranged from low to high. For many biomarker candidates, critical information regarding dose response, correlation with habitual food intake, and reproducibility over time is yet unknown. The nutritional epidemiology field will benefit from the development of novel methods to combine single biomarkers to generate biomarker panels in combination with self-reported data. The most promising dietary biomarker candidates that reflect commonly consumed foods and food components for application in epidemiological studies were identified, and research required for their full validation was summarized.

A metabolomic investigation of serum perfluorooctane sulfonate and perfluorooctanoate.

BACKGROUND: Exposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. METHODS: Metabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses). RESULTS: The meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10-5 and 4.6x10-5, respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10-10 and 2.0x10-8, respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10-15, 1.1x10-17), and lignoceroylcarnitine (C24) (P = 2.6x10-8, 6.2x10-6). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10-112 and 6.8x10-13, respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10-14, 2.3x10-6). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment. CONCLUSIONS: In this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects.

Characteristics of Cancer Epidemiology Studies That Employ Metabolomics: A Scoping Review.

An increasing number of cancer epidemiology studies use metabolomics assays. This scoping review characterizes trends in the literature in terms of study design, population characteristics, and metabolomics approaches and identifies opportunities for future growth and improvement. We searched PubMed/MEDLINE, Embase, Scopus, and Web of Science: Core Collection databases and included research articles that used metabolomics to primarily study cancer, contained a minimum of 100 cases in each main analysis stratum, used an epidemiologic study design, and were published in English from 1998 to June 2021. A total of 2,048 articles were screened, of which 314 full texts were further assessed resulting in 77 included articles. The most well-studied cancers were colorectal (19.5%), prostate (19.5%), and breast (19.5%). Most studies used a nested case-control design to estimate associations between individual metabolites and cancer risk and a liquid chromatography-tandem mass spectrometry untargeted or semi-targeted approach to measure metabolites in blood. Studies were geographically diverse, including countries in Asia, Europe, and North America; 27.3% of studies reported on participant race, the majority reporting White participants. Most studies (70.2%) included fewer than 300 cancer cases in their main analysis. This scoping review identified key areas for improvement, including needs for standardized race and ethnicity reporting, more diverse study populations, and larger studies.

Metabolomic Profiling of an Ultraprocessed Dietary Pattern in a Domiciled Randomized Controlled Crossover Feeding Trial.

BACKGROUND: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health. OBJECTIVES: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification. METHODS: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m2] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs. RESULTS: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP. CONCLUSIONS: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.