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Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women’s Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N-acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N-acetyl-glutamate, allantoin, N-acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine-N-oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development.

Technology-assisted dietary assessment has the potential to improve the accuracy of self-reported dietary intake. This study evaluates MealScan3D (MS3D), a mobile device-based food recording system, which uses three-dimensional images to obtain food volumes and an application to capture algorithm-driven food intake data. Participants (n = 179) were randomly assigned and trained to record three meals using either MS3D or a written food record (WFR). Generous amounts of standardized meals were provided, and participants self-selected portions for each food. The weights of provided and uneaten/leftover foods were used to determine true intake. For total energy intake (three meals combined), validity (Pearson correlation) was significantly higher for MS3D vs. the WFR (p < 0.001); when interpreted as the percentage of variance in energy intake explained, MS3D explained 84.6% of true variance, a 25.3% absolute and 42.6% relative increase over the 59.3% explained by the WFR. For 9 of 15 individual foods, the Pearson correlations between true and reported portion size estimates were significantly larger for MS3D than the WFR. Bias was smaller (intercepts were closer to the means) for 9 of 15 foods and the regression coefficients for 10 of 15 foods were significantly closer to 1.0 in the MS3D arm. MS3D is feasible for dietary assessment and may provide improvements in accuracy compared to WFRs.

Abstract Background Higher physical activity levels are associated with lower breast cancer-specific mortality. In addition, the metabolic syndrome is associated with higher breast cancer-specific mortality. Whether the physical activity association with breast cancer mortality is modified by number of metabolic syndrome components (cardiometabolic risk factors) in postmenopausal women with early-stage breast cancer remains unknown. Methods Cardiovascular risk factors included high waist circumference, hypertension, high cholesterol, and diabetes. Breast cancers were verified by medical record review. Mortality finding were enhanced by serial National Death Index queries. Cox proportional hazards regression models were used to estimate associations between baseline physical activity and subsequent breast cancer-specific and overall mortality following breast cancer diagnosis in Women’s Health Initiative participants. These associations were examined after stratifying by cardiometabolic risk factor group. Results Among 161,308 Women’s Health Initiative (WHI) participants, 8543 breast cancers occurred after 9.5 years (median) follow-up in women, additionally with information on cardiometabolic risk factors and physical activity at entry. In multi-variable analyses, as measured from cancer diagnosis, higher physical activity levels were associated with lower all-cause mortality risk (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78–0.95, trend P

Low total energy expenditure (TEE) has been a hypothesized risk factor for weight gain, but longitudinal repeatability of TEE is incompletely understood. Here the authors report that TEE is repeatable for adults, but not for children, and increases in TEE (adjusted for fat-free mass, fat mass, age and sex) are not associated with body composition changes in short-term longitudinal analyses.

Abstract Background Many of the 3.8 million breast cancer survivors in the United States experience long‐term side effects of cancer therapy including peripheral neuropathy (PN). We assessed the prevalence and predictors of PN among women with breast cancer followed in the Women's Health Initiative's Life and Longevity After Cancer survivorship cohort. Methods The study population included 2420 women with local (79%) or regional (21%) stage disease. Presence of PN was based on the reports of “nerve problems and/or tingling sensations” after treatment and PN severity was assessed using the Functional Assessment of Cancer Therapy‐Gynecologic Oncology Group/Neurotoxicity instrument. Logistic regression analysis was used to evaluate the socio‐demographic and clinical factors associated with PN prevalence and severity. Results Initial breast cancer treatment included surgery‐only (21%), surgery and radiation (53%), or surgery and chemotherapy (±radiation) (26%). Overall, 17% of women reported PN occurring within days (30%), months (46%), or years (24%) after treatment and 74% reported ongoing symptoms at a median of 6.5 years since diagnosis. PN was reported by a larger proportion of chemotherapy recipients (33%) compared to those who had surgery alone (12%) or surgery+radiation (11%) (p

Summary: Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (−10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p

Demographic and clinical factors influence the metabolome. The discovery and validation of disease biomarkers are often challenged by potential confounding effects from such factors. To address this challenge, we investigated the magnitude of the correlation between serum and urine metabolites and demographic and clinical parameters in a well-characterized observational cohort of 444 post-menopausal women participating in the Women’s Health Initiative (WHI). Using LC-MS and lipidomics, we measured 157 aqueous metabolites and 756 lipid species across 13 lipid classes in serum, along with 195 metabolites detected by GC-MS and NMR in urine and evaluated their correlations with 29 potential disease risk factors, including demographic, dietary and lifestyle factors, and medication use. After controlling for multiple testing (FDR < 0.01), we found that log-transformed metabolites were mainly associated with age, BMI, alcohol intake, race, sample storage time (urine only), and dietary supplement use. Statistically significant correlations were in the absolute range of 0.2–0.6, with the majority falling below 0.4. Incorporation of important potential confounding factors in metabolite and disease association analyses may lead to improved statistical power as well as reduced false discovery rates in a variety of data analysis settings.

Abstract We examined cross-sectional associations between arm lymphedema symptoms and health-related quality of life (HRQoL) in the Health, Eating, Activity and Lifestyle (HEAL) Study. 499 women diagnosed with localized or regional breast cancer at ages 35–64 years completed a survey, on average 40 months after diagnosis, querying presence of lymphedema, nine lymphedema-related symptoms, e.g., tension, burning pain, mobility loss, and warmth/redness, and HRQoL. Analysis of covariance models were used to assess HRQoL scores in relation to presence of lymphedema and lymphedema-related symptoms. Lymphedema was self-reported by 137 women, of whom 98 were experiencing lymphedema at the time of the assessment. The most common symptoms were heaviness (52%), numbness (47%), and tightness (45%). Perceived physical health was worse for women reporting past or current lymphedema than those reporting no lymphedema (P-value

We evaluated associations of the Empirical Dietary Index for Hyperinsulinemia (EDIH), Empirical Dietary Inflammatory Pattern (EDIP) and Healthy Eating Index (HEI2015) and their metabolomics profiles with the risk of total and site-specific cancers. We used baseline food frequency questionnaires to calculate dietary scores among 112,468 postmenopausal women in the Women’s Health Initiative. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals for cancer risk estimation. Metabolomic profile scores were derived using elastic-net regression with leave-one-out cross validation. In over 17.8 years, 18,768 incident invasive cancers were adjudicated. Higher EDIH and EDIP scores were associated with greater total cancer risk, and higher HEI-2015 with lower risk: HRQ5vsQ1(95% CI): EDIH, 1.10 (1.04–1.15); EDIP, 1.08 (1.02–1.15); HEI-2015, 0.93 (0.89–0.98). The multivariable-adjusted incidence rate difference(Q5vsQ1) for total cancer was: +52 (EDIH), +41 (EDIP) and −49 (HEI-2015) per 100,000 person years. All three indices were associated with colorectal cancer, and EDIH and EDIP with endometrial and breast cancer risk. EDIH was further associated with luminal-B, ER-negative and triple negative breast cancer subtypes. Dietary patterns contributing to hyperinsulinemia and inflammation were associated with greater cancer risk, and higher overall dietary quality, with lower risk. The findings warrant the testing of these dietary patterns in clinical trials for cancer prevention among postmenopausal women.

Abstract Introduction: Transdisciplinary (TD) research and community-based participatory research (CBPR) represent promising investigative approaches to ameliorate health disparities. Public investments in team-based TD research to address multifactorial public health problems have increased over the last two decades. Similarly, recognition that community participation in research and social action is essential to promoting health equity is reflected in increased prioritization of community engagement in research and practice. Yet, models that describe and guide the combined TD and CBPR approach are lacking. Methods: We utilized a qualitative, convergent parallel case study design that included document reviews and one-on-one interviews to assess how investigators from the Centers for Population Health and Health Disparities (CPHHD) initiative integrated TD team science and CBPR in their work, and what they perceived as the impact of that work on health equity. Results: Twenty-five CPHHD investigators and National Institutes of Health program staff participated in a one-on-one interview. Document and interview data informed the development of an iterative conceptual model of TD CBPR comprising five domains: problem focus, contexts, collaboration and partnership, outcomes, and societal impact of TD CBPR. Conclusions: TD team science and CBPR are integrally related; combining principles of both can facilitate more efficient, equitable progress toward team outcomes, improved population health, and increased health equity. This model could assist researchers and public health practitioners in designing community-relevant, scientifically rigorous research with practical implications for improving health and quality of life among marginalized populations.

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Abstract Background Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk. Methods Cox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years. Results Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses. Conclusion These findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.

Consumption of dietary lignans has been associated with reduced risk of chronic diseases, although the underlying mechanisms are unclear. We sought to determine if urinary excretion of ENL, the predominant microbial metabolite of dietary lignans, was associated with plasma protein abundance using a cross-sectional design based on data and plasma collected from 80 healthy participants in a randomized crossover, controlled feeding study. Proteomic analysis was performed on plasma samples collected at the end of each of two diet periods (160 samples total) using a customized antibody array corresponding to 2072 unique proteins. GC-MS was used to measure ENL excretion in 24-h urine samples collected in tandem with plasma. Linear mixed models tested the association between urinary enterolignan excretion and plasma protein abundance. Subsequently, over-representation analysis was conducted considering 17 a priori pathways with putative associations with enterolignan bioactivity in an exploratory approach. Controlling the false discovery rate at 10%, ENL excretion was inversely associated with seven proteins (FCRL5, PSCA, GAB1, LAPTM5, CCS, REG4, CEACAM1), and positively associated with two proteins (WAS and FBLN5). Over-representation analysis revealed associations of ENL excretion with estrogen and TNF signaling pathways, which were not significant after adjustment for false discovery. These ENL-associated proteins and pathways have potential implications in cancer prevention.

The glycemic index (GI) reflects the relative ability of carbohydrates to raise blood glucose. We utilized a controlled feeding study to assess the impact of the dietary GI on β-cell function in adults with prediabetes (17F/18M, mean ± SEM: BMI 32.44 ± 0.94 kg/m2, age 54.2 ± 1.57 years). Following a 2 week Control diet (GI = 55–58), participants were randomized to either a 4 week low GI (LGI: GI < 35, n = 17) or high GI (HGI: GI > 70, n = 18) diet (55% of energy from carbohydrate/30% fat/15% protein). The data from 4 h meal tolerance tests (MTTs) underwent mathematical modeling to assess insulin sensitivity, insulin secretion and β-cell function. Glucose concentrations during the MTT decreased on the LGI diet (p < 0.001) and trended to increase on the HGI diet (p = 0.14; LGI vs. HGI p < 0.001), with parallel changes in insulin and C-peptide concentrations. Total insulin secretion, adjusted for glucose and insulin sensitivity, increased on the LGI diet (p = 0.002), and trended lower on the HGI diet (p = 0.10; LGI vs. HGI p = 0.001). There was no significant diet effect on insulin sensitivity or other measures of β-cell function. Total insulin clearance increased on the LGI diet (p = 0.01; LGI vs. HGI p < 0.001). We conclude that short-term consumption of an LGI diet reduced glucose exposure and insulin secretion but had no impact on measures of β-cell function.

Background: Meta-analyses of observational studies associate adherence to several dietary patterns with cognitive health. However, limited evidence from full scale, randomized controlled trials precludes causal inference regarding dietary effects on cognitive function. Methods: The Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, in 48,835 postmenopausal women, included a subset of 1,606 WHI Memory Study (WHIMS) participants >= 65 years old, to assess low-fat dietary pattern influence on global cognitive function, evaluated with annual screening (Modified Mini–Mental State Examinations [3MSE]). Participants were randomized by a computerized, permuted block algorithm, stratified by age group and center, to a dietary intervention (40%) to reduce fat intake to 20% of energy and increase fruit, vegetable and grain intake or usual diet comparison groups (60%). The study outcome was possible cognition impairment (failed cognitive function screening) through the 8.5 year (median) dietary intervention. Those failing screening received a comprehensive, multi-phase cognitive function assessment to classify as: no cognitive impairment, mild cognitive impairment, or probable dementia. Exploratory analyses examined the composite endpoint of death after possible cognitive impairment through 18.7 years (median) follow-up. The WHI trials are registered at ClinicalTrials.gov:NCT00000611. Findings: Among the 1,606 WHIMS participants, the dietary intervention statistically significantly reduced the incidence of possible cognitive impairment (n = 126; hazard ratio [HR] 0.59 95% confidence interval [CI] 0.38–0. 91, P = 0.01) with HR for dietary influence on subsequent mild cognitive impairment of 0.65 (95% CI 0.35–1.19) and HR of 0.63 (95% CI 0.19–2.10) for probable dementia (PD). Through 18.7 years, deaths from all-causes after possible cognitive impairment were non-significantly lower in the dietary intervention group (0.56% vs 0.77%, HR 0.83 95% CI 0.35 to 2.00, P = 0.16). Interpretation: Adoption of a low-fat eating pattern, representing dietary moderation, significantly reduced risk of possible cognitive impairment in postmenopausal women. Funding: Several Institutes of the US National Institutes of Health. Keywords: Cognition, Dietary modification, Low-fat dietary pattern, Randomized clinical trial, Women's Health Initiative

Background: The goal of the Frequency of Eating and Satiety Hormones (FRESH) Study is to understand the relationship between eating frequency (EF) and biomarkers of appetite and disease risk. This report gives the study rationale and design. Methods: The FRESH study was conducted in n = 50 overweight and obese, but otherwise healthy, male and female adults aged 18–50 years. The protocol included four in-person clinic visits for protocol instruction, blood draws, anthropometry, and meal testing; all other activities were done at home. Participants completed two 21-day phases in random order with a two-week washout between phases. One phase was high EF (6 eating occasions/day) and the other was low EF (3 eating occasions/day). Each phase specified time of day for each eating occasion. Participants prepared their own meals throughout the study using study-provided individualized, structured meal plans ensuring that calories, macronutrients and micronutrients were identical during both study phases. Fasting blood was collected before and after each phase to test intervention effects on the biomarkers. At the end of each phase participants also completed extended appetite testing with meals prepared by the study clinic. Results: Participants were recruited using print, radio, and digital ads. 60 participants consented to enroll; 10 dropped out due to work or school scheduling conflicts and 50 (target sample size) completed the study. Compliance was assessed by completion of daily on-line meal plan checklists. Conclusions: The FRESH study will provide data on whether higher vs. lower daily EF in the context of constant energy and nutrient intake may be harmful or beneficial based on intervention effects on biomarkers of health and disease risk. Keywords: Eating frequency, Appetite, Randomized controlled trial, Cross-over design

Although the gut microbiome has been associated with dietary patterns linked to health, microbial metabolism is not well characterized. This ancillary study was a proof of principle analysis for a novel application of metaproteomics to study microbial protein expression in a controlled dietary intervention. We measured the response of the microbiome to diet in a randomized crossover dietary intervention of a whole-grain, low glycemic load diet (WG) and a refined-grain, high glycemic load diet (RG). Total proteins in stools from 9 participants at the end of each diet period (n = 18) were analyzed by LC MS/MS and proteins were identified using the Human Microbiome Project (HMP) human gut microbiome database and UniProt human protein databases. T-tests, controlling for false discovery rate (FDR)

Background and Aims: The association of fatty acids with coronary heart disease (CHD) has been examined, mainly through dietary measurements, and has generated inconsistent results due to measurement error. Large observational studies and randomized controlled trials have shown that plasma phospholipid fatty acids (PL-FA), especially those less likely to be endogenously synthesized, are good biomarkers of dietary fatty acids. Thus, PL-FA profiles may better predict CHD risk with less measurement error. Methods: We performed a matched case-control study of 2428 postmenopausal women nested in the Women’s Health Initiative Observational Study. Plasma PL-FA were measured using gas chromatography and expressed as molar percentage (moL %). Multivariable conditional logistic regression was used to calculate odds ratios (95% CIs) for CHD associated with 1 moL % change in PL-FA. Results: Higher plasma PL long-chain saturated fatty acids (SFA) were associated with increased CHD risk, while higher n-3 polyunsaturated fatty acids (PUFA) were associated with decreased risk. No significant associations were observed for very-long-chain SFA, monounsaturated fatty acids (MUFA), PUFA n-6 or trans fatty acids (TFA). Substituting 1 moL % PUFA n-6 or TFA with an equivalent proportion of PUFA n-3 were associated with lower CHD risk. Conclusions: Higher plasma PL long-chain SFA and lower PUFA n-3 were associated with increased CHD risk. A change in diet by limiting foods that are associated with plasma PL long-chain SFA and TFA while enhancing foods high in PUFA n-3 may be beneficial in CHD among postmenopausal women.

Novel technology-based dietary assessment methods use volume estimates of foods to assess dietary intake. However, the nutrient content of standard databases is based on food weight. The goal of this study is to evaluate the accuracy of the United States Department of Agriculture National Nutrient Database for Standard Reference (USDA-SR) estimates of volume and the corresponding macronutrient content of the foods. The weights of 35 individual food volumes were measured (on trial) and compared to the USDA-SR-determined weight for the food volume. Macronutrient content corresponding to the trial weight and the USDA-SR weight for the food volume (USDA) were determined using the USDA-SR, and the differences were calculated. There were statistically significant differences between the USDA and trial weights for 80% of foods measured. Calorie estimates by USDA weight were significantly lower than that of trial weight for 54% of foods but were significantly greater for 26% of foods. Differences in macronutrient estimates by trial and USDA weight varied by food type. These findings suggest that nutrient databases based on food weight may not provide accurate estimates of dietary intake when assessed using food volumes. Further development of image-assisted dietary assessment methods which measure food volumes will necessitate evaluation of the accuracy of the processes used to convert weight to volume in nutrient databases.

To inform strategies to improve the dietary intakes of populations, robust evaluations of interventions are required. This paper is drawn from a workshop held at the International Society of Behavioral Nutrition and Physical Activity 2017 Annual Meeting, and highlights considerations and research priorities relevant to measuring dietary outcomes within intervention studies. Self-reported dietary data are typically relied upon in such studies, and it is recognized that these data are affected by random and systematic error. Additionally, differential error between intervention and comparison groups or pre- and post-intervention can be elicited by the intervention itself, for example, by creating greater awareness of eating or drinking occasions or the desire to appear compliant. Differential reporting can render the results of trials incorrect or inconclusive by leading to biased estimates and reduced statistical power. The development of strategies to address intervention-related biases requires developing a better understanding of the situations and population groups in which interventions are likely to elicit differential reporting and the extent of the bias. Also needed are efforts to expand the feasibility and applications of biomarkers to address intervention-related biases. In the meantime, researchers are encouraged to consider the potential for differential biases in dietary reporting in a given study, to choose tools carefully and take steps to minimize and/or measure factors such as social desirability biases that might contribute to differential reporting, and to consider the implications of differential reporting for study results.

Combined intakes of specific dietary fiber and fat subtypes protect against colon cancer in animal models. We evaluated associations between self-reported individual and combinations of fiber (insoluble, soluble, and pectins, specifically) and fat (omega-6, omega-3, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), specifically) and colorectal cancer (CRC) risk in the Women’s Health Initiative prospective cohort (n = 134,017). During a mean 11.7 years (1993–2010), 1952 incident CRC cases were identified. Cox regression models computed multivariate adjusted hazard ratios to estimate the association between dietary factors and CRC risk. Assessing fiber and fat individually, there was a modest trend for lower CRC risk with increasing intakes of total and insoluble fiber (p-trend 0.09 and 0.08). An interaction (p = 0.01) was observed between soluble fiber and DHA + EPA, with protective effects of DHA + EPA with lower intakes of soluble fiber and an attenuation at higher intakes, however this association was no longer significant after correction for multiple testing. These results suggest a modest protective effect of higher fiber intake on CRC risk, but not in combination with dietary fat subtypes. Given the robust results in preclinical models and mixed results in observational studies, controlled dietary interventions with standardized intakes are needed to better understand the interaction of specific fat and fiber subtypes on colon biology and ultimately CRC susceptibility in humans.