Erikka Loftfield

Ph.D., M.P.H.

National Cancer Instiute

Research Fellow

PLCO (Learn more about this study)

2018-0018

Jul 30, 2018

Multivitamin Use and Mortality: Leveraging Repeat Measures and Metabolomic Profiles to Clarify the Impact of Multivitamin Use on Mortality Risk

In the United States, an estimated 31% of adults use multivitamins (MV), with prevalence of use even higher among women and older Americans. As people take multivitamins to enhance health and prevent disease, studies of the effects of MV use on total and cause-specific mortality are the ultimate measures of public health impact. However, despite widespread use, the scientific evidence on MV use and mortality is mixed and highly controversial, and several important questions remain unresolved. First, it is unclear how MV use changes over time among individuals, and how such changes may affect disease. One issue of concern is that patients with diagnosed disease may alter their MV intake, either increasing or decreasing their use because of perceived benefit or harm. Second, confounding by healthy lifestyle remains a major concern as MV users often differ from nonusers with respect to diet, smoking, physical activity and obesity. Finally, there is a lack of mechanistic knowledge regarding the physiologic effects of MV use in people and how these effects may be related to disease.

Therefore, to address the questions of how changes in MV use and confounding by lifestyle impact mortality estimates, I will conduct a large-scale prospective investigation of MV use and total and cause-specific mortality using three geographically diverse, U.S. cohorts (i.e., the NIH-AARP Diet and Health Study cohort; the Agricultural Health Study (AHS) cohort; and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial cohort) with repeat assessments of MV use and extensive follow-up for mortality outcomes. With a combined sample size exceeding 670,000 adults and 107,000 deaths, the proposed study will be well-powered to test associations among population subgroups including those who are adherent or nonadherent to healthy lifestyle recommendations. The first part of this project has been approved by each of the three cohorts and the data has already been obtained. Next, to address the question of physiologic effects of MV use, I propose systematically examining how 50 long-term self-reported MV users differ from 50 MV nonusers, frequency matched on age and sex, using non-targeted metabolomics to analyze serially collected serum samples and compare levels of more than 1000 small molecules, representing the major classes of exogenous and endogenous metabolites, across three or more years of follow-up. Although, several promising serum biomarkers of multivitamin use, namely pyridoxate and pantothenate, have been identified using a non-targeted metabolomics approach for biomarker identification, no prior studies have explored the long-term variation in metabolomic profiles between MV users and nonusers. Because each participant in the proposed sub-study will have three serum samples, collected over three or more years, with two collections coinciding with self-reported MV use, I will be able to characterize short-term (i.e., 1-year) and long-term (i.e., ≥3-year) profile stability within and between individuals as well as within and between groups of MV users and nonusers. Such characterizations will advance mechanistic knowledge of the effects of MV use on metabolism and disease.

Specific Aims: The study will address the following aims using already obtained secondary data (Aims 1A & 1B) and the proposed biomarker data to be generated from PLCO serum samples (Aims 2A & 2B):

1. Aim 1A: Prospectively evaluate the association of daily MV use, as compared to nonuse, with total mortality and cause-specific mortality from the 10 leading causes of death in the United States in three large, geographically diverse cohorts.

2. Aim 1B: Investigate the impact of: 1) changes in MV use over time on risk of mortality using follow-up assessments, and 2) confounding by healthy lifestyle using detailed information on smoking, dietary intake, physical activity and obesity and leveraging the very large sample size to perform stratified analyses with sufficient statistical power to detect modest associations.

3. Aim 2A: Compare the metabolite profiles of long-term, daily MV users to long-term MV nonusers using serial serum samples collected over an extended period (≥3 years).

4. Aim 2B: Assess short-term (i.e., 1-year) and long-term (i.e., ≥3-year) stability of metabolite profiles within and between groups of daily MV users and MV nonusers.