Measurement Error Corrected Sodium and Potassium Intake Estimation Using 24-Hour Urinary ExcretionNovelty and Significance
Epidemiological studies of the association of sodium and potassium intake with cardiovascular disease risk have almost exclusively relied on self-reported dietary data. Here, 24-hour urinary excretion assessments are used to correct the dietary self-report data for measurement error under the assumption that 24-hour urine recovery provides a biomarker that differs from usual intake according to a classical measurement model. Under this assumption, dietary self-reports underestimate sodium by 0% to 15%, overestimate potassium by 8% to 15%, and underestimate sodium/potassium ratio by ≈20% using food frequency questionnaires, 4-day food records, or three 24-hour dietary recalls in Women’s Health Initiative studies. Calibration equations are developed by linear regression of log-transformed 24-hour urine assessments on corresponding log-transformed self-report assessments and several study subject characteristics. For each self-report method, the calibration equations turned out to depend on race and age and strongly on body mass index. After adjustment for temporal variation, calibration equations using food records or recalls explained 45% to 50% of the variation in (log-transformed) 24-hour urine assessments for sodium, 60% to 70% of the variation for potassium, and 55% to 60% of the variation for sodium/potassium ratio. These equations may be suitable for use in epidemiological disease association studies among postmenopausal women. The corresponding signals from food frequency questionnaire data were weak, but calibration equations for the ratios of sodium and potassium/total energy explained ≈35%, 50%, and 45% of log-biomarker variation for sodium, potassium, and their ratio, respectively, after the adjustment for temporal biomarker variation and may be suitable for cautious use in epidemiological studies.
A strong association of high sodium and low potassium intake with elevated blood pressure and hypertension has been established in epidemiological studies and randomized controlled trials,1,2 but epidemiological studies of these associations with cardiovascular disease (CVD) incidence and mortality have been less consistent.3,4 However, epidemiological studies of these associations have nearly all relied on self-report dietary data. The accuracy of dietary assessment for these nutrients has been reported to depend on individual characteristics, as well as behavioral and environmental factors.5,6 The limitations of dietary data have stimulated some studies to use 24-hour urinary excretions, instead, for sodium and potassium intake estimation. Specifically, the Trials of Hypertension Prevention (TOHP) collaborative group reported a positive association between the urinary sodium/potassium excretion ratio and CVD incidence, but there were only 193 incident events, and associations with sodium and potassium separately were not significant.7 A study among people with established CVD or diabetes mellitus used urinary excretion data, and had a larger number of CVD events, but the relevance to disease risk in healthy populations is unclear.8
For reasons of cost, 24-hour urine excretions are typically not collected by all enrollees in large epidemiological cohort studies. Instead, one can use 24-hour urine excretions in a subsample of moderate size to develop calibration equations that aim to correct the self-report data for random and systematic bias aspects of their measurement error. These equations can then be used to develop calibrated intake estimates throughout study cohorts for use in disease association analyses.
The regression calibration approach9–11 just outlined assumes the biomarker consumption estimate, here that based on log-transformed 24-hour urinary recovery, to equal the targeted consumption, which here is defined as usual daily intake for a specified time period, plus error that has mean zero and is independent of the targeted quantity and of other study subject characteristics, a so-called classical measurement error model. This measurement model allows the objective measure to differ considerably from its target, but in a manner that is independent and random among study subjects. With log-transformation, the approach would be little affected if the measurement error mean was allowed to be nonzero to make a provision for nutrient excretion through sweat or feces.
However, note that 24-hour urine excretions are somewhat controversial as individual consumption biomarkers, especially for sodium. For example, within-population correlations for paired 24-hour urine assessments separated by several months were 0.50 for potassium but only 0.30 for sodium in the TONE (Trial of Nonpharmacologic Interventions in the Elderly) trial.5 A controlled human feeding study involving randomly fluctuating sodium consumption found a correlation of 0.55 between 24-hour urine sodium and corresponding actual dietary intake, with improved agreement when using multiple 24-hour urine collections for several days.12 A recent experiment, involving a constant sodium intake for some months, revealed some important rhythmicities of 24-hour sodium excretion of duration >24 hours, possibly because of within-population tissue sodium retention variations over time.13 It seems plausible that these variations are independent and random among study subjects, but data available in this research effort do not allow this assumption to be tested. In addition to a classical measurement model for log-transformed 24-hour urine assessment, the measurement model used here14 includes a more flexible measurement model for the corresponding self-report data to allow for systematic biases with body mass index15 and with other factors.
Women’s Health Initiative (WHI) resources provide an opportunity to develop calibration equations in the context of postmenopausal women in the United States: Nutrition biomarker studies within WHI cohorts collected 24-hour urine specimens, which were analyzed for sodium and potassium content for this report, and also assessed dietary habits using each of food frequency questionnaires (FFQs), 4-day food records (4DFRs), and three 24-hour dietary recalls (24HRs). Twenty-percent reliability subsamples repeated the biomarker protocols ≈6 months after the initial application, allowing study of calibration equation improvement with replicate 24-hour urine and dietary data. Calibration equations from these biomarker substudies will be presented in this report. A subsequent report will relate the resulting calibrated consumption estimates, using equations developed here, to CVD risks in WHI cohorts.
Materials and Methods
The design of the WHI clinical trial and observational study (OS) and enrollee characteristics at WHI enrollment have been presented.16–18 All women were postmenopausal and in the age range 50 to 79 years when enrolled at 40 US clinical centers during 1993 to 1998. The clinical trial enrolled 68 132 women to either or both of the Dietary Modification (DM) trial (48 835 women) or to overlapping postmenopausal hormone therapy trials (27 347 women). The companion WHI OS is a prospective cohort study that enrolled 93 676 postmenopausal women in the age range 50 to 79 years from 1994 to 1998. The clinical trial and OS cohorts were drawn from essentially the same catchment populations, with substantial overlap in baseline data collection and in outcome ascertainment procedures19 during cohort follow-up. The WHI FFQ20 was administered at baseline and 1 year in the DM trial, and approximately every 3 years thereafter during the trial intervention period (ended April 8, 2005), and was administered at baseline and 3 years in the OS. A 4DFR was obtained at baseline for women in the DM trial as a part of eligibility determination, and 24HRs were obtained for certain subsets of DM trial participants.
Nutrition Biomarker Substudies in the WHI
The data considered here are derived from 2 nutrition biomarker substudies within WHI cohorts. The Nutrient Biomarker Study (NBS), conducted from 2004 to 2006, included 544 women at 12 WHI clinical centers. It enrolled 50% of women from the DM intervention group and 50% from the usual diet comparison group of the DM trial cohort, with few additional eligibility or exclusionary criteria.21 The NBS aims to evaluate measurement properties of the WHI FFQ and to correct FFQ consumption estimates for measurement error.
The Nutrition and Physical Activity Assessment Study (NPAAS) enrolled 450 postmenopausal women from the OS and was conducted from 2007 to 2009.22 Women were recruited at 9 WHI clinical centers, 8 of which also participated in the NBS. Black and Hispanic women were oversampled, as were women in the extremes of body mass index (BMI) and relatively younger postmenopausal women. NPAAS was designed to evaluate and to compare the measurement properties of the FFQ, 4DFR, and three 24HRs.
Women were excluded from either biomarker study for having any medical condition precluding participation, weight instability, or travel plans during the study period. In both studies a 20% reliability subsample repeated the entire study protocol at ≈6 months after the original protocol application.
NBS and NPAAS Protocol and Procedures
The study protocol for both studies involved 2 clinical center visits separated by a 2-week period, along with at-home activities. Detailed descriptions of visit content and schedule have been published.21,22 Participants collected 24-hour urine excretion on the day before the second clinic visit. At the second visit, completeness of the 24-hour urine collections was assessed by self-report of missed or spilled collections and para-aminobenzoic acid. In the 16 NBS patients and in the 7 NPAAS patients, urine collections were considered incomplete and excluded from present analyses. Figure S1 in the online-only Data Supplement provides further detail on the data collection schedule in NBS and in NPAAS.
Sodium and potassium urine analyses were performed by ion-selective electrode.23 For NBS, the assays were conducted by Pharmaceutical Product Development Global Central Laboratories in Highland Heights, Kentucky, and for NPAAS at the University of Washington Laboratory Medicine. The coefficients of variation in the NBS were 11.6% for sodium and 10.7% for potassium based on 32 blind duplicate pairs, and in NPAAS the coefficients of variations were 4.3% for sodium and 5.9% for potassium based on 24 and 26 blind duplicate pairs, respectively. Total energy expenditure during the 2-week protocol was estimated by a doubly labeled water procedure.21,22
Dietary Assessment in NBS and NPAAS
Dietary assessment procedures, including the WHI FFQ,15 4DFR, and 24HRs, as applied in NBS and NPAAS, have been described in some detail.21,22 Dietary data from each of the 3 methods were analyzed for nutrient content using the University of Minnesota’s Nutrition Coordinating Center’s Nutrition Data Systems for Research (NDS-R).
Calibration equations were developed that target usual consumption during ≈1-year period for each of sodium, potassium, and the sodium/potassium ratio. Additional equations were developed for the corresponding ratios of sodium and potassium/total energy consumption. For each nutritional variable, these equations were developed from linear regression of the log-transformed biomarker assessment on the corresponding log-transformed dietary assessment and other factors. The signal strength from the self-report was judged by its regression coefficient and by the percent of biomarker variation (R2) in the study sample explained by the self-report assessment. The overall regression R2 was used to examine the ability of associated calibrated consumption estimates to recover the biomarker variation. Adjusted R2 values that allow for random variation in the biomarker because of differences between consumption and biomarker values during the 24-hour urine collection period, or to consumption variations over time within the overall targeted time period, are calculated by dividing unadjusted R2 values by the correlation between paired log-transformed biomarker values from the pertinent 20% reliability stubstudy.22
Additional calibration equations were developed using only data from the reliability subsamples. These equations arise from linear regression of the average of the paired log-transformed biomarker values on the average of the corresponding paired log-transformed self-report values and other factors. Adjusted R2 values from these analyses are calculated by multiplying unadjusted R2 values by 0.5+0.5ρ–1, where ρ is the correlation between paired log-transformed biomarker values from the reliability subsample.
In making these calculations, daily food record and recall estimates were averaged before log-transformation. Also, values for log-transformed biomarker and self-report assessments that fall outside the interquartile range for the variable by more than twice its width were excluded as outliers.
Calibration equations arising from FFQ assessments from the nonoverlapping NBS and NPAAS data sets were compared using likelihood ratio tests based on the combined data set. Bootstrap procedures (10 000 bootstrap samples) were used to compare regression coefficients across dietary assessment instruments. All P values are 2 sided.
The overall WHI protocol, and protocols for NBS and NPAAS, was approved by the institutional review committees of participating institutions, and participating women provided written informed consent for their overall and biomarker study activities.
Table 1 shows the distribution of women enrolled in NBS and NPAAS according to characteristics assessed at the time of biomarker study participation. About two thirds of the women were overweight or obese. Note the larger fraction of black and Hispanic women in NPAAS was compared with those in NBS.
Table 2 shows geometric means and associated 95% confidence intervals for the 24-hour urine measures and for each of the dietary assessments, for sodium, potassium, and the sodium/potassium ratio. Corresponding statistics are shown on the right side of Table 2 for the ratio of each self-report to the biomarker. Compared with the 24-hour urine measures, sodium is underestimated by 15% (NBS) and 10% (NPAAS) by the WHI FFQ, by 8% using three 24HRs, and by a nonsignificant 2% using the 4DFR. In comparison, potassium is overestimated by ≥10% by each of the dietary assessment approaches, and the sodium/potassium ratio is underestimated by ≈20% by each assessment procedure. Also (not shown) in NBS, the FFQ underestimation in sodium was not significantly different between the DM trial comparison arm and the intervention arm, as was also the case for the potassium overestimation. However, the underestimation of sodium/potassium ratio was somewhat larger in the NBS intervention arm (P=0.02).
Table S1 examines whether these biases depend on study subject characteristics, based on linear regression of log(self-report)–log(biomarker) on the listed characteristics. As for energy and protein estimation,21,22 the most influential characteristics were BMI, age, and race. Sodium underestimation with the FFQ was considerably larger among black and Hispanic women when compared with white women and was larger among relatively younger women and also among women having a high BMI. Somewhat similar patterns were evident for sodium estimation based on 24HRs, but biases in relation to these factors were not significant for the 4DFR.
There were few clear systematic biases for potassium estimation. Systematic biases were evident with each of the dietary assessment procedures for the sodium/potassium ratio. This ratio was underestimated to a greater extent among women with high BMI when using the FFQ, and the underestimation was greater among black and Hispanic women with each of the 3 assessment methods.
Besides age, BMI, and race, other factors, such as DM trial randomization (for NBS), dietary supplement use, smoking status, education, and income also, have some relationship to reporting bias.
Table 3 presents adjusted R2 values for the dietary self-report assessments and the overall fitted model from linear regression of log(biomarker) on log(self-report) and other study subject characteristics. The left side of Table 3 gives these adjusted R2 values based on the initial biomarker and dietary assessments in the 2 biomarker studies, whereas the right side of Table 3 provides corresponding information based on the paired biomarker and dietary assessments in the 20% reliability subsample component of these studies.
From the left side of Table 3, one sees that the FFQ sodium assessments explain little of the 24-hour urine sodium variation (adjusted R2 of 5.3% and 3.5% in NBS and NPAAS, respectively), whereas the 4DFR and 24HR assessments provide an explanation or ≈20% to 25% of this variation. The adjusted R2 values are somewhat larger for potassium, but are still only ≈15% to 20% from the FFQ assessment when compared with 50% to 60% from food records or recalls. The FFQ adjusted R2 values for the sodium/potassium ratio were ≈25% when compared with 40% to 45% for the 4DFR or 24HRs. Detail on these calibration equations, sufficient to allow intake estimates to be calculated from the dietary self-report data and study subject characteristics, is given in Table S2. These show that BMI contributes significantly to sodium calibration when used with any of the 3 assessment procedures, as did age with the FFQ and 24HR assessments. For potassium, race contributed significantly to the calibration using any of the assessment methods, as did several other variables with the FFQ assessment. Race also contributed to the calibration for the sodium/potassium ratio, as did education for each of the self-report assessments, and as did dietary supplement use.
The total regression adjusted R2 values on the left side of Table 3 support the use of calibrated consumption estimates from the 4DFR and the 24HRs for each of the 3 nutritional variables and possibly also those from FFQs for the sodium/potassium ratios.
We compared FFQ calibration equations between NBS and NPAAS. A likelihood ratio test of equality of all coefficients was not significant for sodium (P=0.59) or potassium (P=0.22). The NPAAS sodium/potassium ratio calibration equation did not differ from that for the DM comparison group in NBS, whereas this ratio was underestimated to a greater extent for the DM intervention group in NPAAS (P=0.02).
Figures S2 and S3 show paired log(biomarker) and log(self-report) values from the 20% reliability subsample of the 2 biomarker studies. The 24-hour urine correlations between paired values were 0.32 (NBS) and 0.31 (NPAAS) for sodium, 0.46 for potassium, and 0.56 for the sodium/potassium ratio, based on the 111 women in the NBS reliability substudy and the 88 women in the NPAAS reliability subsample. The adjusted R2 values on the right side of Table 3 are based on reliability subsample data only and are less precisely estimated because of the much reduced sample sizes. The adjusted R2 values for the self-report increase when using the replicate 4DFR and 24HR assessments, but improvement is not evident when using FFQs. Total regression adjusted R2 values are in the 60% to 80% range using food records or recalls for each of the 3 dietary variables. Details of these calibration equations, which would require replicate dietary data for application, are given in Table S3.
Table S4 augments the calibration equations of Table S2 by including interaction terms between the log(self-report) and race. Some moderate interactions were suggested for each of sodium, potassium, and their ratio, with weaker self-report signals from minority women, especially for the 4DFR-based equations.
Additional analyses considered whether the use of certain medications may imply needed refinements to the calibration equations of Table S2. Participating WHI women were asked to provide medication information from 2008 to 2009. For NPAAS women, this inventory mostly took place 1 to 2 years after their biomarker study participation. There were 56, 53, 101, and 89 NPAAS women who reported the use of β blockers, calcium channel blockers, antihypertensives (including angiotensin II receptor agonists, angiotensin-converting enzyme inhibitors), and diuretics (including sodium channel blockers and potassium-sparing diuretics, aldosterone antagonists), respectively, for an immediately preceding time period in excess of 1 year. The NPAAS calibration equation analyses were repeated excluding 11 corticosteroid users of >1-year duration and including indicator variables for each of the 4 antihypertensive categories listed above. The significance levels for testing zero coefficients for the 4 indicator variables were, respectively, 0.90, 0.49, 0.54, and 0.78 for sodium; 0.35, 0.98, 0.98, and 0.40 for potassium; and 1.00, 0.71, 0.66, and 0.80 for the sodium/potassium ratio.
Table S5 shows analyses corresponding to Table S2 for sodium and potassium divided by total energy consumption. This involves regression of the log-transformed 24-hour urine measures divided by the doubly labeled water estimate of total energy on the corresponding self-report nutrient intake/total energy ratio and the other listed variables. Results were similar to those in Table S2 without such energy adjustment, but BMI did not contribute significantly to the sodium calibration. Adjusted R2 values for FFQ assessments were somewhat larger than those shown on the right side of Table 3 with adjusted R2 values of 25% to 45% for sodium/energy and 45% to 55% for potassium/energy.
The analyses presented here assume that log-transformed 24-hour urine sodium and potassium provide estimates of corresponding log-transformed usual intake (eg, for a 1-year period), with measurement error that is independent of intake and study subject characteristics, such as BMI, age, race, and education. This assumption cannot be tested with data available in the WHI biomarker studies. For sodium, this assumption has some support from an earlier human feeding study,12 but tissue retention rythmicities over time periods >24 hours13 need to be included in the biomarker error component, along with actual consumption variations across 24-hour periods. The rather modest correlations (0.32 in NBS and 0.31 in NPAAS; Figures S2 and S3) between log-transformed 24-hour urinary sodium between paired urine samples collected at time points separated by ≈6 months in time presumably reflect both of these sources of variation. Corresponding correlations were larger for log-transformed 24-hour urinary potassium (0.53 in NBS and 0.46 in NPAAS).
Under this biomarker modeling assumption, simple linear calibration equations are shown here to capture much of the variation in usual daily nutrient consumption in WHI biomarker studies when these equations use intake estimates from 4DFRs or three 24HRs. In fact, the adjusted R2 values for sodium, potassium, and the sodium/potassium ratio (Table 3, left side) are comparable with those for energy and protein22 using their well-established biomarkers. These adjusted R2 values can be increased further if replicate 4DFRs or replicate sets of three 24HRs are available with suitable temporal separation (Table 3, right side).
In comparison, the ability of FFQ-based dietary data to explain variations in corresponding 24-hour urine measures is limited especially for sodium, and this ability is not improved using replicate FFQs. This limitation may reflect the ubiquitous nature of sodium in the food supply that may not be adequately captured by a FFQ generic list of non–brand-named foods.24 Also, the WHI FFQ did not specify sodium-reduced food products within the food list and did not ask about salt added during cooking or at the table. Despite these limitations, there was a useful signal from the FQ data for the ratios of sodium and potassium/total energy, and corresponding calibration equations (Table S5) can be recommended, along with that for the sodium/potassium ratio (Table S2) for cautious use in disease association studies.
CVD association studies in WHI cohorts using calibrated estimates for sodium, potassium, and their ratio are planned for the near future. The question of portability of calibration equations to cohorts beyond that in which they were generated has not received much attention in the nutritional epidemiology literature to date. A pooled nutritional biomarker study involving nutritional biomarker studies in the United States, including NBS and NPAAS, is currently underway, and will examine this topic for energy, protein, sodium, and potassium.
The strengths of this study include the sizeable nutritional biomarker studies, nested within large and well-characterized cohorts of postmenopausal women. Limitations include the single 24-hour urine collection among most of these women and uncertainty about the adequacy of 24-hour sodium and potassium excretion as usual intake biomarkers. In view of this uncertainty, additional work to develop biomarkers of usual sodium and potassium intake further is recommended.
Hypertension associations with sodium and potassium consumption are well established, but epidemiological studies to relate these consumptions to CVD risk have been mixed, possibly because of their typical reliance on self-reported dietary consumption. Nutrient biomarker studies within WHI cohorts of postmenopausal women are used to develop estimates of sodium and potassium intake and their ratio that aim to correct self-report estimates for measurement error. These calibrated estimates seem to be able to reproduce much of the variation in average daily consumption estimates for ≈1-year period of time and to be suitable for use in association studies with disease outcomes. Such association studies will be performed in the near future in the WHI setting, which entails >160 000 postmenopausal women who have been followed since the 1990s. These association analyses may help to refine sodium and potassium dietary recommendations and could help to stimulate needed improvements in the food supply for chronic disease risk reduction.
For a list of all the investigators who have contributed to Women’s Health Initiative science, please visit https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf.
Drs Van Horn, Tinker, Neuhouser, and Prentice planned the analyses and obtained Women’s Health Initiative (WHI) approvals. Dr Huang served as principal data analyst and contributed to article drafting. Dr Prentice coordinated the effort, including article drafting. Drs Tinker, Huang, and Neuhouser investigated and used WHI resources to explore the influence of hypertensive medications on findings. All authors contributed to critical revisions of the article, leading to several improvements, for example in the areas of biomarker quality control (Dr Carbone), statistical model building (Dr Thomas), alternate data analyses and data interpretation (Dr Mossavar-Rahmani).
Sources of Funding
This work was partially supported by grants CA119171 and CA53996 from the National Cancer Institute. Women’s Health Initiative (WHI) Program support is provided by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services (contract HHSN268201100046C). Decisions about study design, data collection and analysis, interpretation of the results, the preparation of the article, or the decision to submit the article for publication resided with committees comprised of WHI investigators that included National Heart, Lung, and Blood Institute representatives.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.02218/-/DC1.
- Received August 13, 2013.
- Revision received September 23, 2013.
- Accepted October 29, 2013.
- © 2013 American Heart Association, Inc.
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Novelty and Significance
What Is New?
Equations are developed to correct self-reported intake of sodium, potassium, and their ratio for measurement error in dietary assessment.
These calibration equations are provided for dietary data from each of food frequency questionnaires, 4-day food records, and three 24-hour dietary recalls.
What Is Relevant?
Measurement error in dietary assessment has impeded study of the risk of cardiovascular and other diseases in relation to sodium and potassium consumption.
This article shows that the signals from certain types of dietary self-report data are sufficiently strong for reliable sodium and potassium consumption estimation when combined with other readily available study subject data.
The work provides important infrastructure for research to strengthen dietary recommendations about sodium and potassium.
Self-report intake data that have been corrected for measurement error can be calculated from the calibration equations presented here, for use in full-scale disease association studies among postmenopausal women. Analyses of this type from the national Women’s Health Initiative (160 000 women) will be reported separately.