24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk.

BACKGROUND: The relation between sodium intake and cardiovascular disease remains controversial, owing in part to inaccurate assessment of sodium intake. Assessing 24-hour urinary excretion over a period of multiple days is considered to be an accurate method. METHODS: We included individual-participant data from six prospective cohorts of generally healthy adults; sodium and potassium excretion was assessed with the use of at least two 24-hour urine samples per participant. The primary outcome was a cardiovascular event (coronary revascularization or fatal or nonfatal myocardial infarction or stroke). We analyzed each cohort using consistent methods and combined the results using a random-effects meta-analysis. RESULTS: Among 10,709 participants, who had a mean (±SD) age of 51.5±12.6 years and of whom 54.2% were women, 571 cardiovascular events were ascertained during a median study follow-up of 8.8 years (incidence rate, 5.9 per 1000 person-years). The median 24-hour urinary sodium excretion was 3270 mg (10th to 90th percentile, 2099 to 4899). Higher sodium excretion, lower potassium excretion, and a higher sodium-to-potassium ratio were all associated with a higher cardiovascular risk in analyses that were controlled for confounding factors (P≤0.005 for all comparisons). In analyses that compared quartile 4 of the urinary biomarker (highest) with quartile 1 (lowest), the hazard ratios were 1.60 (95% confidence interval [CI], 1.19 to 2.14) for sodium excretion, 0.69 (95% CI, 0.51 to 0.91) for potassium excretion, and 1.62 (95% CI, 1.25 to 2.10) for the sodium-to-potassium ratio. Each daily increment of 1000 mg in sodium excretion was associated with an 18% increase in cardiovascular risk (hazard ratio, 1.18; 95% CI, 1.08 to 1.29), and each daily increment of 1000 mg in potassium excretion was associated with an 18% decrease in risk (hazard ratio, 0.82; 95% CI, 0.72 to 0.94). CONCLUSIONS: Higher sodium and lower potassium intakes, as measured in multiple 24-hour urine samples, were associated in a dose-response manner with a higher cardiovascular risk. These findings may support reducing sodium intake and increasing potassium intake from current levels. (Funded by the American Heart Association and the National Institutes of Health.).

Portfolio Diet Score and Risk of Cardiovascular Disease: Findings From 3 Prospective Cohort Studies.

BACKGROUND: The plant-based Portfolio dietary pattern includes recognized cholesterol-lowering foods (ie, plant protein, nuts, viscous fiber, phytosterols, and plant monounsaturated fats) shown to improve several cardiovascular disease (CVD) risk factors in randomized controlled trials. However, there is limited evidence on the role of long-term adherence to the diet and CVD risk. The primary objective was to examine the relationship between the Portfolio Diet Score (PDS) and the risk of total CVD, coronary heart disease (CHD), and stroke. METHODS: We prospectively followed 73 924 women in the Nurses' Health Study (1984-2016), 92 346 women in the Nurses' Health Study II (1991-2017), and 43 970 men in the Health Professionals Follow-up Study (1986-2016) without CVD or cancer at baseline. Diet was assessed using validated food frequency questionnaires at baseline and every 4 years using a PDS that positively ranks plant protein (legumes), nuts and seeds, viscous fiber sources, phytosterols (mg/day), and plant monounsaturated fat sources, and negatively ranks foods high in saturated fat and cholesterol. RESULTS: During up to 30 years of follow-up, 16 917 incident CVD cases, including 10 666 CHD cases and 6473 strokes, were documented. After multivariable adjustment for lifestyle factors and a modified Alternate Healthy Eating Index (excluding overlapping components), comparing the highest with the lowest quintile, participants with a higher PDS had a lower risk of total CVD (pooled hazard ratio [HR], 0.86 [95% CI, 0.81-0.92]; Ptrend<0.001), CHD (pooled HR, 0.86 [95% CI, 0.80-0.93]; Ptrend=0.0001), and stroke (pooled HR, 0.86 [95% CI, 0.78-0.95]; Ptrend=0.0003). In addition, a 25-percentile higher PDS was associated with a lower risk of total CVD (pooled HR, 0.92 [95% CI, 0.89-0.95]), CHD (pooled HR, 0.92 [95% CI, 0.88-0.95]), and stroke (pooled HR, 0.92 [95% CI, 0.87-0.96]). Results remained consistent across sensitivity and most subgroup analyses, and there was no evidence of departure from linearity for CVD, CHD, or stroke. In a subset of participants, a higher PDS was associated with a more favorable blood lipid and inflammatory profile. CONCLUSIONS: The PDS was associated with a lower risk of CVD, including CHD and stroke, and a more favorable blood lipid and inflammatory profile, in 3 large prospective cohorts.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Validity and Reproducibility of a Semiquantitative Food Frequency Questionnaire for Measuring Intakes of Foods and Food Groups.

We evaluated the validity and reproducibility of a semiquantitative food frequency questionnaire (FFQ) for measuring intakes of 149 foods and 25 food groups among 736 participants of the Women's Lifestyle Validation Study (WLVS, 2010-2012) and 649 participants of the Men's Lifestyle Validation Study (MLVS, 2011-2013). Validity of the FFQ compared with two 7-day dietary records measured 6 months apart and the reproducibility between 2 FFQs administered 1 year apart (FFQ1 and FFQ2) were assessed using Spearman correlations and intraclass correlation coefficients. The average 1-year reproducibility of FFQ-measured foods was 0.64 in both the WLVS and MLVS. Reproducibility of the food groups (mean = 0.71 among women and 0.72 among men) was generally higher than that for individual foods. Among women, the average validity correlation for individual foods was 0.59 when comparing FFQ2 with the 7-day dietary records. Among men, the corresponding average validity correlation was 0.61. Compared with individual foods, food groups had slightly higher validity correlations in both women (range, 0.45-0.92; mean = 0.61) and men (range, 0.46-0.88; mean = 0.65). This study reaffirms that the FFQ performs well in measuring most foods and food groups and provides data to adjust for measurement errors in epidemiologic studies of foods and food groups.

Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Recreational physical activity and breast cancer risk by menopausal status and tumor hormone receptor status: results from the Nurses' Health Studies.

PURPOSE: Physical activity is associated with lower breast cancer risk, especially in postmenopausal women. Associations in premenopausal women are less well established. METHODS: We evaluated recreational physical activity and breast cancer risk in the Nurses' Health Study (NHS) and NHSII (187,278 women; n = 12,785 breast cancers; follow-up: NHS = 1986-2016, NHSII = 1989-2017) by menopausal status and estrogen (ER) and progesterone (PR) receptor status. Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/week. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Recreational physical activity was inversely associated with breast cancer risk in pre- and postmenopausal women. Higher activity levels were associated with lower risk of ER+/PR + breast cancer in both pre- and postmenopausal women (e.g., total recreational activity, ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83, 95%CI = (0.70-0.99), postmenopausal HR = 0.86 (0.78-0.95); pheterogeneity = 0.97). Results were attenuated with adjustment for current body mass index (BMI) among postmenopausal, but not premenopausal, women (e.g., ≥ 27 vs < 3 MET-h/week, premenopausal HR = 0.83 (0.69-0.98); postmenopausal HR = 0.95 (0.85-1.05); pheterogeneity = 0.99). In analyses of moderate-vigorous activity and breast cancer risk, no heterogeneity by menopausal status was observed (phet ≥ 0.53; e.g., ≥ 27 vs < 3 MET-h/week, ER+/PR+, premenopausal HR = 0.88 (0.69-1.11); postmenopausal HR = 0.71 (0.58-0.88). No associations were observed for ER-/PR- disease. CONCLUSIONS: Recreational physical activity was associated with lower breast cancer risk in both pre- and postmenopausal women, supporting recreational physical activity as an accessible, modifiable exposure associated with reduced breast cancer risk regardless of menopausal status.

Specific dairy foods and risk of frailty in older women: a prospective cohort study.

BACKGROUND: Dairy contains a complex mixture of lipids, proteins, and micronutrients. Whether habitual dairy consumption is associated with health benefits is not well established. Since dairy is high in nutrients that are potentially protective against frailty, the association between dairy products and the risk of frailty is of interest. METHODS: We analyzed data from 85,280 women aged ≥ 60 years participating in the Nurses' Health Study. Consumption of milk, yogurt, and cheese was obtained from repeated food frequency questionnaires administered between 1980 and 2010. Frailty was defined as having at least three of the following five criteria from the FRAIL scale: fatigue, low strength, reduced aerobic capacity, having ≥ 5 chronic illnesses, and a weight loss of ≥ 5%. The occurrence of frailty was assessed every four years from 1992 to 2018. Cox proportional hazard models were used to examine the association between the intake of dairy foods and frailty. RESULTS: During follow-up we identified 15,912 incident cases of frailty. Consumption of milk or yogurt was not associated with the risk of frailty after adjustment for lifestyle factors, medication use, and overall diet quality. Cheese consumption was positively associated with risk of frailty [relative risk (95% confidence interval) for one serving/day increment in consumption: 1.10 (1.05, 1.16)]. Replacing one serving/day of milk, yogurt, or cheese with one serving/day of whole grains, nuts, or legumes was associated with a significant lower risk of frailty, while replacing milk, yogurt, or cheese with red meat or eggs was associated with an increased risk. When milk was replaced with a sugar-sweetened or artificially sweetened beverage, a greater risk of frailty was observed, while replacing milk with orange juice was associated with a lower risk of frailty. CONCLUSIONS: The results suggest that the association between milk, yogurt, and cheese and frailty partly depends on the replacement product. Habitual consumption of milk or yogurt was not associated with risk of frailty, whereas cheese consumption may be associated with an increased risk.

All-cause and cause-specific mortality risk and loss in life expectancy associated with incident type 2 diabetes onset age and duration.

BACKGROUND: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. METHODS: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow-up Study, leveraging repeated measurements throughout up to 40 years of follow-up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), and kidney disease (8.55, 1.98-36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. CONCLUSION: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy.

Red Meat Intake and the Risk of Cardiovascular Diseases: A Prospective Cohort Study in the Million Veteran Program.

BACKGROUND: Red meat consumption was associated with an increased risk of cardiovascular disease (CVD) in prospective cohort studies and a profile of biomarkers favoring high CVD risk in short-term controlled trials. However, several recent systematic reviews and meta-analyses concluded with no or weak evidence for limiting red meat intake. OBJECTIVES: To prospectively examine the associations between red meat intake and incident CVD in an ongoing cohort study with diverse socioeconomic and racial or ethnic backgrounds. METHODS: Our study included 148,506 participants [17,804 female (12.0%)] who were free of cancer, diabetes, and CVD at baseline from the Million Veteran Program. A food frequency questionnaire measured red meat intakes at baseline. Nonfatal myocardial infarction and acute ischemic stroke were identified through a high-throughput phenotyping algorithm, and fatal CVD events were identified by searching the National Death Index. RESULTS: Comparing the extreme categories of intake, the multivariate-adjusted relative risks of CVD was 1.18 (95% CI: 1.01, 1.38; P-trend < 0.0001) for total red meat, 1.14 (95% CI: 0.96, 1.36; P-trend = 0.01) for unprocessed red meat, and 1.29 (95% CI: 1.04, 1.60; P-trend = 0.003) for processed red meat. We observed a more pronounced positive association between red meat intake and CVD in African American participants than in White participants (P-interaction = 0.01). Replacing 0.5 servings/d of red meat with 0.5 servings/d of nuts, whole grains, and skimmed milk was associated with 14% (RR: 0.86; 95% CI: 0.83, 0.90), 7% (RR: 0.93; 95% CI: 0.89, 0.96), and 4% (RR: 0.96; 95% CI: 0.94, 0.99) lower risks of CVD, respectively. CONCLUSIONS: Red meat consumption is associated with an increased risk of CVD. Our findings support lowering red meat intake and replacing red meat with plant-based protein sources or low-fat dairy foods as a key dietary recommendation for the prevention of CVD.

Differences in metabolomic profiles between Black and White women in the U.S.: Analyses from two prospective cohorts.

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences ≥ |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

Validity and reproducibility of the PERSIAN Cohort food frequency questionnaire: assessment of major dietary patterns.

BACKGROUND: Dietary patterns, encompassing an overall view of individuals' dietary intake, are suggested as a suitable means of assessing nutrition's role in chronic disease development. The aim of this study was to evaluate the validity and reproducibility of a food frequency questionnaire (FFQ) designed for use in the Prospective Epidemiological Research Studies in IrAN (PERSIAN), by comparing major dietary patterns assessed by the FFQ with a reference method. METHODS: Study participants included men and women who enrolled in the PERSIAN Cohort Study at seven of the eighteen centers. These centers were chosen to include dietary variations observed among the different Iranian ethnic populations. Two FFQ were completed for each participant over a one-year study period (FFQ1 upon enrollment and FFQ2 at the end of the study), with 24 interviewer-administered 24-hour dietary recalls (24 h) being completed monthly in between. Spearman correlation coefficients (SCC) were used comparing FFQs 1 and 2 to the 24 h to assess validity, while FFQ1 was compared to FFQ2 to assess reproducibility of the questionnaire. RESULTS: Three major dietary patterns-Healthy, Low Protein/High Carb and Unhealthy-were identified, accounting for 70% of variance in the study population. Corrected SCC ranged from 0.31 to 0.61 in the validity and from 0.34 to 0.57 in reproducibility analyses, with the first two patterns, which accounted for over 50% of population variance, correlated at above 0.5 in both parameters, showing acceptable findings. CONCLUSIONS: The PERSIAN Cohort FFQ is suitable for identification of major dietary patterns in the populations it is used for, in order to assess diet-disease relationships.

Vegetarian and vegan diets: benefits and drawbacks.

Plant-based diets have become increasingly popular thanks to their purported health benefits and more recently for their positive environmental impact. Prospective studies suggest that consuming vegetarian diets is associated with a reduced risk of developing cardiovascular disease (CVD), diabetes, hypertension, dementia, and cancer. Data from randomized clinical trials have confirmed a protective effect of vegetarian diets for the prevention of diabetes and reductions in weight, blood pressure, glycosylated haemoglobin and low-density lipoprotein cholesterol, but to date, no data are available for cardiovascular event rates and cognitive impairment, and there are very limited data for cancer. Moreover, not all plant-based foods are equally healthy. Unhealthy vegetarian diets poor in specific nutrients (vitamin B12, iron, zinc, and calcium) and/or rich in highly processed and refined foods increase morbidity and mortality. Further mechanistic studies are desirable to understand whether the advantages of healthy, minimally processed vegetarian diets represent an all-or-nothing phenomenon and whether consuming primarily plant-based diets containing small quantities of animal products (e.g. pesco-vegetarian or Mediterranean diets) has beneficial, detrimental, or neutral effects on cardiometabolic health outcomes. Further, mechanistic studies are warranted to enhance our understanding about healthy plant-based food patterns and the biological mechanisms linking dietary factors, CVD, and other metabolic diseases.

Consumption of olive oil and risk of breast cancer in U.S. women: results from the Nurses' Health Studies.

BACKGROUND: Olive oil consumption may reduce breast cancer risk, but it is unclear whether olive oil is beneficial for breast cancer prevention in populations outside of Mediterranean regions, namely in the U.S., where the average consumption of olive oil is low compared with Mediterranean populations. We examined whether olive oil intake was associated with breast cancer risk in two prospective cohorts of U.S. women. METHODS: We used multivariable-adjusted time-varying Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence interval (CI) for breast cancer among 71,330 (Nurses' Health Study, 1990-2016) and 93,295 women (Nurses' Health Study II, 1991-2017) who were free of cancer at baseline. Diet was assessed by a validated semi-quantitative food frequency questionnaire every 4 years. RESULTS: During 3,744,068 person-years of follow-up, 9,638 women developed invasive breast cancer. The multivariable-adjusted HR (95% CI) for breast cancer among women who had the highest consumption of olive oil (>1/2 tablespoon/d or >7 g/d) compared with those who never or rarely consumed olive oil, was 1.01 (0.93, 1.09). Higher olive oil consumption was not associated with any subtype of breast cancer. CONCLUSION: We did not observe an association between higher olive oil intake and breast cancer risk in two large prospective cohorts of U.S. women, whose average olive oil consumption was low. Prospective studies are needed to confirm these findings and to further investigate whether different varieties of olive oil (e.g., virgin and extra virgin olive oil) may play a role in breast cancer risk.

Different operationalizations of the 2018 WCRF/AICR cancer prevention recommendations and risk of cancer.

BACKGROUND: The standardized scoring system assessing adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations assigns equal weight for each recommendation, thereby giving higher weight to dietary factors collectively (5 points) than adiposity (1 point) and physical activity (1 point). An alternative score assigning equal weights to the adiposity, physical activity, alcohol, and other dietary (composite) recommendations may better predict cancer associations. METHODS: We examined associations between standardized and alternative scores with cancer risk in two US prospective cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. RESULTS: During 28 years of follow-up, 16,342 incident cancer cases in women and 8729 cases in men occurred. Individuals in the highest versus lowest quintile of the standardized score had a reduced overall cancer risk (women: HR = 0.89, 95% CI: 0.85, 0.94; men: HR = 0.87, 95% CI: 0.81, 0.94). Results were slightly stronger for the alternative score (women: HR = 0.83, 95% CI: 0.79, 0.87; men: HR = 0.81, 95% CI: 0.75, 0.86). Similar patterns were observed for obesity-related, alcohol-related, smoking-related, and digestive system cancers. CONCLUSIONS: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with lower cancer risk. A score assigning equal weights to the adiposity, physical activity, alcohol, and all remaining diet components yielded stronger associations than the standardized score.

Western-Style Diet, pks Island-Carrying Escherichia coli, and Colorectal Cancer: Analyses From Two Large Prospective Cohort Studies.

BACKGROUND & AIMS: Evidence supports a carcinogenic role of Escherichia coli carrying the pks island that encodes enzymes for colibactin biosynthesis. We hypothesized that the association of the Western-style diet (rich in red and processed meat) with colorectal cancer incidence might be stronger for tumors containing higher amounts of pks+E coli. METHODS: Western diet score was calculated using food frequency questionnaire data obtained every 4 years during follow-up of 134,775 participants in 2 United States-wide prospective cohort studies. Using quantitative polymerase chain reaction, we measured pks+E coli DNA in 1175 tumors among 3200 incident colorectal cancer cases that had occurred during the follow-up. We used the 3200 cases and inverse probability weighting (to adjust for selection bias due to tissue availability), integrated in multivariable-adjusted duplication-method Cox proportional hazards regression analyses. RESULTS: The association of the Western diet score with colorectal cancer incidence was stronger for tumors containing higher levels of pks+E coli (Pheterogeneity = .014). Multivariable-adjusted hazard ratios (with 95% confidence interval) for the highest (vs lowest) tertile of the Western diet score were 3.45 (1.53-7.78) (Ptrend = 0.001) for pks+E coli-high tumors, 1.22 (0.57-2.63) for pks+E coli-low tumors, and 1.10 (0.85-1.42) for pks+E coli-negative tumors. The pks+E coli level was associated with lower disease stage but not with tumor location, microsatellite instability, or BRAF, KRAS, or PIK3CA mutations. CONCLUSIONS: The Western-style diet is associated with a higher incidence of colorectal cancer containing abundant pks+E coli, supporting a potential link between diet, the intestinal microbiota, and colorectal carcinogenesis.

Hypertensive conditions of pregnancy, preterm birth, and premenopausal breast cancer risk: a premenopausal breast cancer collaborative group analysis.

PURPOSE: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group. METHODS: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression. RESULTS: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56). CONCLUSION: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy.

Change in habitual intakes of flavonoid-rich foods and mortality in US males and females.

BACKGROUND: Higher baseline intakes of flavonoid-rich foods and beverages are associated with a lower risk of chronic disease and mortality in observational studies. However, associations between changes in intakes and mortality remain unclear. We aimed to evaluate associations between 8-year changes in intakes of (1) individual flavonoid-rich foods and (2) a composite measure (termed the 'flavodiet') of foods and beverages that are known to be main contributors to flavonoid intake and subsequent total and cause-specific mortality. METHODS: We evaluated associations between 8-year changes in intakes of (1) individual flavonoid-rich foods and (2) a novel 'flavodiet' score and total and cause-specific mortality. We included 55,786 females from the Nurses' Health Study (NHS) and 29,800 males from the Health Professionals Follow-up Study (HPFS), without chronic disease at baseline in our analyses. Using multivariable-adjusted Cox proportional hazard models, we examined associations of 8-year changes in intakes of (1) flavonoid-rich foods and (2) the flavodiet score with subsequent 2-year lagged 6-year risk of mortality adjusting for baseline intakes. Data were pooled using fixed-effects meta-analyses. RESULTS: We documented 15,293 deaths in the NHS and 8988 deaths in HPFS between 1986 and 2018. For blueberries, red wine and peppers, a 5%, 4% and 9% lower risk of mortality, respectively, was seen for each 3.5 servings/week increase in intakes while for tea, a 3% lower risk was seen for each 7 servings/week increase [Pooled HR (95% CI) for blueberries; 0.95 (0.91, 0.99); red wine: 0.96 (0.93, 0.99); peppers: 0.91 (0.88, 0.95); and tea: 0.97 (0.95, 0.98)]. Conversely, a 3.5 servings/week increase in intakes of onions and grapefruit plus grapefruit juice was associated with a 5% and 6% higher risk of total mortality, respectively. An increase of 3 servings per day in the flavodiet score was associated with an 8% lower risk of total mortality [Pooled HR: 0.92 (0.89, 0.96)], and a 13% lower risk of neurological mortality [Pooled HR: 0.87 (0.79, 0.97)], after multivariable adjustments. CONCLUSIONS: Encouraging an increased intake of specific flavonoid-rich foods and beverages, namely tea, blueberries, red wine, and peppers, even in middle age, may lower early mortality risk.

Promoting Reproducibility and Integrity in Observational Research: One Approach of an Epidemiology Research Community.

To increase research reproducibility, sharing of study data, analysis code, and use of standardized reporting are increasingly advocated. However, beyond reproducibility, few initiatives have addressed the integrity of how research is conducted before manuscripts are submitted. We describe a decades-long experience with a comprehensive approach based in an academic research community around prospective cohort studies that is aimed at promoting a culture of integrity in observational research. The approach includes prespecifying hypotheses and analysis plans, which are discussed in the research community and posted; presentation and discussion of analysis results; mandatory analysis code review by a programmer; review of concordance between analysis output and manuscripts by a technical reviewer; and checks of adherence to the process, including compliance with institutional review board requirements and reporting stipulations by the National Institutes of Health. The technical core is based in shared computing and analytic environments with long-term archiving. More than simply a list of rules, our approach promotes research integrity through integrated educational elements, making it part of the "hidden curriculum," by fostering a sense of belonging, and by providing efficiency gains to the research community. Unlike reproducibility checklists, such long-term investments into research integrity require substantial and sustained funding for research personnel and computing infrastructure. Our experiences suggest avenues for how institutions, research communities, and funders involved in observational research can strengthen integrity within the research process.

Performance of the Global Diet Quality Score (GDQS) App in Predicting Nutrient Adequacy and Metabolic Risk Factors among Thai Adults.

BACKGROUND: The Global Diet Quality Score (GDQS) was developed for monitoring nutrient adequacy and diet-related noncommunicable disease risk in diverse populations. A software application (GDQS app) was recently developed for the standardized collection of GDQS data. The application involves a simplified 24-h dietary recall (24HR) where foods are matched to GDQS-food groups using an onboard database, portion sizes are estimated at the food group level using cubic models, and the GDQS is computed. OBJECTIVES: The study aimed to estimate associations between GDQS scores collected using the GDQS app and nutrient adequacy and metabolic risks. METHODS: In this cross-sectional study of 600 Thai males and nonpregnant/nonlactating females (40-60 y), we collected 2 d of GDQS app and paper-based 24HR, food-frequency questionnaires (FFQs), anthropometry, body composition, blood pressure, and biomarkers. Associations between application scores and outcomes were estimated using multiple regression, and application performance was compared with that of metrics scored using 24HR and FFQ data: GDQS, Minimum Dietary Diversity-Women, Alternative Healthy Eating Index-2010, and Global Dietary Recommendations score. RESULTS: In covariate-adjusted models, application scores were significantly (P < 0.05) associated with higher energy-adjusted mean micronutrient adequacy computed using 24HR (range in estimated mean adequacy between score quintiles 1 and 5: 36.3%-44.5%) and FFQ (Q1-Q5: 40.6%-44.2%), and probability of protein adequacy from 24HR (Q1-Q5: 63%-72.5%). Application scores were inversely associated with BMI kg/m2 (Q1-Q5: 26.3-24.9), body fat percentage (Q1-Q5: 31.7%-29.1%), diastolic blood pressure (Q1-Q5: 84-81 mm Hg), and a locally-developed sodium intake score (Q1-Q5: 27.5-24.0 points out of 100); positively associated with high-density lipoprotein cholesterol (Q1-Q5: 49-53 mg/dL) and 24-h urinary potassium (Q1-Q5: 1385-1646 mg); and inversely associated with high midupper arm circumference (Q5/Q1 odds ratio: 0.52) and abdominal obesity (Q5/Q1 odds ratio: 0.51). Significant associations for the application outnumbered those for metrics computed using 24HR or FFQ. CONCLUSIONS: The GDQS app effectively assesses nutrient adequacy and metabolic risk in population surveys.

Influence of analytic methods, data sources, and repeated measurements on the population attributable fraction of lifestyle risk factors.

Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin's formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses' Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin's formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually.