AS498 - Nutrition and physical activity assessment study (NPAAS) Competing renewal
Investigator Names and Contact Information
Marian Neuhouser (mneuhous@fredhutch.org)
Johanna Lampe
Introduction/Intent
NPAAS III (grant period 2016-2020)
This competing renewal of CA119171, "Nutrition and Physical Activity Assessment Study" (NPAAS), continues to focus on the use of biomarkers and regression calibration models to understand the relationships between diet, physical activity and chronic disease risk in postmenopausal women.
Dietary and physical activity patterns are thought to play a major role in the etiology of chronic disease risk in the United States, including risk for major cancers, cardiovascular disease and diabetes. These diseases are among the most prominent contributors to morbidity, health care expenditures and mortality in the United States. Prevention is critical to improving health and reducing costs,11 but credible public health prevention programs and policy initiatives have been hampered by lack of consistency in the many reports on nutrition and activity pattern associations with chronic disease risk. One of the barriers to public health progress, as noted by PAR-12-198, is that both self-reported diet and activity are subject to major random and systematic measurement error. Since observational and interventional studies rely, respectively, on self-report data for determination of primary exposures and for assessment of intervention adherence, poor self-report assessments severely limit the ability to draw inferences concerning disease associations, and limit the ability to identify compelling strategies and policies for chronic disease risk reduction.
Over the past nine years we have made progress in understanding the relationship of specific nutrition and physical activity variables with the risk of various cancers, cardiovascular disease and diabetes among other outcomes. Our work uses objective biomarkers in regression calibration models to correct self-report data for random and systematic measurement biases. This work has provided evidence, for example, for strong positive associations of energy consumption, and strong inverse associations of activity-related energy expenditure, with risk of many of these diseases. These associations were mostly not evident without measurement error correction. However, heretofore, suitable quantitative biomarkers have been available only for a few components of diet (e.g., total energy, protein, potassium, sodium) and physical activity (e.g., total activity-related energy expenditure).
In the current funding period we conducted a controlled feeding study in n=153 Women's Health Initiative (WHI) participants living near Seattle, WA, for the purpose of developing biomarkers for additional dietary variables, using post-feeding period blood and urine specimens. The design of the controlled feeding study allowed us to precisely quantitate the nutrients and foods that participants consumed over the two-week feeding period, with study diets chosen to approximate each woman's usual diet. Potential biomarkers for a small set of additional nutrients were listed in our feeding study grant proposal. Recently, with support from the Women's Health Initiative, we were able to develop also blood- and urine- based metabolite profiles for the 153 women, providing a rich resource for the potential development of biomarkers for a broad range of nutrients/foods. In the upcoming funding period, our goal will be to carry out an examination of the association of each nutrient for which a suitable metabolomic biomarker can be established, with the incidence of important cancers and other chronic diseases in WHI cohorts.
Specific Aims
The specific aims for the upcoming grant period are:
2.1 For each nutrient for which an intake biomarker can be established using current grant cycle feeding study data, we will evaluate the ability to develop calibrated intake estimates from regression of the biomarker on corresponding dietary self-report (e.g., food frequency questionnaire or four-day food record data) and other study participant characteristics, using specimens and data from the 450 WHI women at 9 clinic locations, collected in the previous cycle of this research program.
2.2 For each nutrient for which a biomarker can be established, and a corresponding calibration procedure meeting criteria can be developed, to conduct association studies to relate the estimated nutrient intake to the risk of major cancers, cardiovascular diseases and diabetes in WHI cohorts (161,000 postmenopausal women).
2.3 For each nutrient for which a biomarker can be established, to determine metabolite-based consumption estimates using stored blood and urine specimens and metabolite profiles from cancer cases (n=708) and controls (n=708) from a WHI sub-cohort where both blood and urine specimens are available. These case-control analyses will allow novel direct examinations of nutrient consumption in relation to cancer risk in a manner that avoids dietary self-report data. These case-control analyses will focus on breast, colorectal, ovarian and endometrial cancers – cancers expected to have some diet-related etiology.
2.4 To examine blood- and urine-based metabolomic profiles more generally in relation to the risk of breast, colorectal, ovarian, and endometrial cancer in the same case-control sample, without regard to the role of specific metabolites in nutrient biomarker specification. This work offers the possibility of novel risk marker identification for these cancers through the ability of targeted and global metabolite profiles to reflect dietary intake variations as well as metabolic variations due to genetics or to microbiome or lifestyle influences.
Introduction/Intent
NPAAS IV (information for AS498C; grant period 2020-2024)
This competing renewal of CA119171-12 “Nutrition and Physical Activity Assessment Study” (NPAAS), continues to focus on dietary biomarkers, regression calibration models, and new biostatistical approaches to characterize measurement error in diet and physical activity assessment with applications toward understanding the relationships between diet, physical activity and chronic disease in postmenopausal women.
In previous NPAAS funding cycles we implemented doubly labeled water and 24-hour urine collection protocols in 450 participants in the Women’s Health Initiative (WHI) Observational Study (NPAAS-OS), 88 (20%) of whom repeated the protocol six months later. We also implemented a controlled feeding study plus the doubly labeled water and 24-hour urine protocols in 153 WHI participants (NPAAS-FS). The data and biospecimens collected from these women (i) supported our discovery of new biomarkers of diet, (ii) informed our progress in understanding systematic measurement error in self-reported diet and physical activity assessment and (iii) guided new statistical approaches to correct for the systematic measurement error in dietdisease association analyses.1-9 Novel nutritional biomarkers from the current funding cycle include the discovery that serum carbon and nitrogen stable isotope ratios (CIR and NIR, respectively) from NPAAS-FS specimens are useful objective biomarkers of animal protein and fish/seafood,10 and have strong potential for added sugars when measured in specific molecules. We also used NPAAS-FS data and specimens to report that a combination of serum phospholipid fatty acids and the total energy estimate from the doubly labeled water protocol yields good estimates for several nutrients including total carbohydrate and total saturated fat,2 nutrients for which biomarker identification has been elusive. Regarding application to disease associations, we used NPAAS to report that when 24-hour urine measures of sodium and the sodium:potassium ratio were used in regression calibration equations and applied to > 48,000 WHI participants with a mean of 12 years of follow-up, each 20% increase in sodium intake had a hazard ratio = 1.36 (95% CI 1.02, 1.82) for heart failure and each 20% increase in potassium had a hazard ratio = 0.85 (95% CI 0.73., 0.99) for coronary heart disease.3 Finally, we continued to develop statistical methods for disease association studies using dietary biomarkers.12 These method developments and applications are consistent with the objectives of PA-18-856.
Evidence gaps remain in multiple areas of diet and physical activity assessment methodology. One specific gap is identifying objective measures of dietary patterns. The 2015 Dietary Guidelines for Americans provided guidance on how consumers can improve their overall eating patterns (i.e., the complete combination of foods and beverages in their diet).13 To date, few studies have systematically characterized objective biomarkers of these diet patterns and the food groups inherent to the patterns. Identifying and validating a panel of dietary intake biomarkers that can be used to monitor adherence to Dietary Guidelines recommendations will allow for objective evaluation of the association between the dietary patterns and risk of cancer, cardiovascular disease and other chronic diseases. Other methodologic gaps exist in development of statistical methods for using nutritional biomarkers in chronic disease association studies. Therefore, in the upcoming funding period, our goals will be to identify candidate metabolite biomarkers of specific foods and dietary patterns, create additional regression calibration equations, test the calibrated food intakes and dietary patterns in disease association studies in the WHI and develop and apply new statistical methods to our studies.
Specific Aims
The specific aims for the upcoming grant period are:
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To further develop and evaluate additional candidate biomarkers of foods, nutrients and other dietary compounds informed by data from the NPAAS-FS.
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To measure serum CIR, NIR and amino acid CIR as biomarkers of fish/seafood, animal protein and added sugars in the NPAAS-OS and to apply these measures to test associations with risk of caner, cardiovascular disease, and type 2 diabetes in WHI cohorts of postmenopausal women.
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To identify and evaluate candidate nutritional biomarkers of healthy eating patterns (e.g., Healthy Eating Index, Alternative Mediterranean Diet Score) for testing associations between these eating patterns and risk of cancer, cardiovascular disease and diabetes in postmenopausal women in the WHI cohorts.
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To develop novel statistical methods for (1) applying newly developed intake biomarkers to assess chronic disease associations in a calibration mode; and for (2) intake biomarker identification using metabolomic profiles, while acknowledging missing and mismeasured aspects of data from valuable global platforms.
Expected Impact: New biomarkers of diet together with development of new statistical methods will contribute to advancing important research priorities for understanding diet and its effects on chronic disease risk.14
