Nutritional epidemiology and the Women's Health Initiative: a review

Abstract

The dietary modification (DM) clinical trial, within the Women's Health Initiative (WHI), studied a low-fat dietary pattern intervention that included guidance to increase vegetables, fruit, and grains. This study was motivated in part from uncertainty about the reliability of observational studies examining the association between dietary fat and chronic disease risk by using self-reported dietary data. In addition to this large trial, which had breast and colorectal cancer as its primary outcomes, a substantial biomarker research effort was initiated midway in the WHI program to contribute to nutritional epidemiology research more broadly. Here we review and update findings from the DM trial and from the WHI nutritional biomarker studies and examine implications for future nutritional epidemiology research. The WHI included the randomized controlled DM trial (n = 48,835) and a prospective cohort observational (OS) study (n = 93,676), both among postmenopausal US women, aged 50-79 y when enrolled during 1993-1998. Also reviewed is a nutrition and physical activity assessment study in a subset of 450 OS participants (2007-2009) and a related controlled feeding study among 153 WHI participants (2010-2014). Long-term follow-up in the DM trial provides evidence for intervention-related reductions in breast cancer mortality, diabetes requiring insulin, and coronary artery disease in the subset of normotensive healthy women, without observed adverse effects or changes in all-cause mortality. Studies of intake biomarkers, and of biomarker-calibrated intake, suggest important associations of total energy intake and macronutrient dietary composition with the risk for major chronic diseases among postmenopausal women. Collectively these studies argue for a nutrition epidemiology research agenda that includes major efforts in nutritional biomarker development, and in the application of biomarkers combined with self-reported dietary data in disease association analyses. We expect such efforts to yield novel disease association findings and to inform disease prevention approaches for potential testing in dietary intervention trials. This trial was registered at clinicaltrials.gov as NCT00000611.

Keywords: biomarker; cancer; cardiovascular disease; diabetes; diet assessment; dietary intervention; energy consumption; macronutrient; measurement error; women's health.

Published by Oxford University Press on behalf of the American Society for Nutrition 2021.

Figures

FIGURE 1

Monitored and other important outcomes in the WHI Dietary Modification Trial (n = 48,835) during its 8.5-y (median) intervention period (A), and over cumulative follow-up (B) of 13.4 y (median) for CVD outcomes and ∼20 y (median) for other outcomes. Summary statistics are shown for randomly assigned groups. HRs, 95% CIs, and significance levels (P values) derive from Cox regression models with baseline hazard stratified on age at randomization (50–54, 55–59, 60–69, 70–79), self-reported ethnicity (white, black, other), hysterectomy status (yes, no), prior disease (if applicable), random assignment status in the WHI hormone therapy trials, and study phase (intervention, extension phase 1, extension phase 2; time-dependent). Time to event is time from random assignment. P values are from a score (log-rank) test. Analyses for diabetes outcomes were restricted to participants without prevalent diabetes at baseline (n = 45,595). Note that results for CHD have been shown (14) to be confounded by post–random assignment use of statins. As elaborated in the narrative, CHD incidence is lower in the intervention than the comparison group in the subset of baseline healthy, normotensive women where evidence of confounding was lacking. CHD, coronary heart disease; CVD, cardiovascular disease; WHI, Women's Health Initiative.