Criterion validity of wrist accelerometry for assessing energy intake via the intake-balance technique.

BACKGROUND: Intake-balance assessments measure energy intake (EI) by summing energy expenditure (EE) with concurrent change in energy storage (ΔES). Prior work has not examined the validity of such calculations when EE is estimated via open-source techniques for research-grade accelerometry devices. The purpose of this study was to test the criterion validity of accelerometry-based intake-balance methods for a wrist-worn ActiGraph device. METHODS: Healthy adults (n = 24) completed two 14-day measurement periods while wearing an ActiGraph accelerometer on the non-dominant wrist. During each period, criterion values of EI were determined based on ΔES measured by dual X-ray absorptiometry and EE measured by doubly labeled water. A total of 11 prediction methods were tested, 8 derived from the accelerometer and 3 from non-accelerometry methods (e.g., diet recall; included for comparison). Group-level validity was assessed through mean bias, while individual-level validity was assessed through mean absolute error, mean absolute percentage error, and Bland-Altman analysis. RESULTS: Mean bias for the three best accelerometry-based methods ranged from -167 to 124 kcal/day, versus -104 to 134 kcal/day for the non-accelerometry-based methods. The same three accelerometry-based methods had mean absolute error of 323-362 kcal/day and mean absolute percentage error of 18.1-19.3%, versus 353-464 kcal/day and 19.5-24.4% for the non-accelerometry-based methods. All 11 methods demonstrated systematic bias in the Bland-Altman analysis. CONCLUSIONS: Accelerometry-based intake-balance methods have promise for advancing EI assessment, but ongoing refinement is necessary. We provide an R package to facilitate implementation and refinement of accelerometry-based methods in future research (see paulhibbing.com/IntakeBalance).

Commercial Devices Provide Estimates of Energy Balance with Varying Degrees of Validity in Free-Living Adults.

BACKGROUND: The challenges of accurate estimation of energy intake (EI) are well-documented, with self-reported values 12%-20% below expected values. New approaches rely on gold-standard assessments of the other components of energy balance, energy expenditure (EE) and energy storage (ES), to estimate EI. OBJECTIVES: The purpose of this study was to evaluate the validity, repeatability, and measurement error of consumer devices when estimating energy balance in a free-living population. METHODS: Twenty-four healthy adults (14 women, 10 men; mean ± SD age: 30.7 ± 8.2 y) completed two 14-d assessment periods, including assessments of EE and ES using gold-standard [doubly labeled water (DLW) and DXA] and commercial devices [Fitbit Alta HR activity monitor (Alta) and Fitbit Aria wireless body composition scale (Aria)], and of EI by dietician-administered recalls. Accuracy and validity were assessed using Spearman correlation, interclass correlation, mean absolute percentage error, and equivalency testing. We also applied linear measurement error modeling including error in gold-standard devices and within-subject repeated-measures design to calibrate consumer devices and quantify error. RESULTS: There was moderate to strong agreement for EE between the Fitbit Alta and DLW at each time point (rs = 0.82 and 0.66 for Times 1 and 2, respectively). There was weak agreement for ES between the Fitbit Aria and DXA (rs = 0.15 and 0.49 for Times 1 and 2, respectively). Correlations between methods to assess EI ranged from weak to strong, with agreement between the DXA/DLW-calculated EI and dietary recalls being the highest (rs = 0.63 for Time 1 and 0.73 for Time 2). Only EE from the Fitbit Alta at Time 1 was equivalent to the DLW value using equivalency testing. CONCLUSIONS: Commercial devices provide estimates of energy balance in free-living adults with varying degrees of validity compared to gold-standard techniques. EE estimates were the most robust overall, whereas ES estimates were generally poor.

The relationship between moderate to vigorous physical activity and metabolic syndrome: a Bayesian measurement error approach.

Metabolic Syndrome (MetS) is a serious condition that can be an early warning sign of heart disease and Type 2 diabetes. MetS is characterized by having elevated levels of blood pressure, cholesterol, waist circumference, and fasting glucose. There are many articles in the literature exploring the relationship between physical activity and MetS, but most do not consider the measurement error in the physical activity measurements nor the correlations among the MetS risk factors. Furthermore, previous work has generally treated MetS as binary, rather than directly modeling the risk factors on their measured, continuous space. Using data from the National Health and Nutrition Examination Survey (NHANES), we explore the relationship between minutes of moderate to vigorous physical activity (MVPA) and MetS risk factors. We construct a measurement error model for the accelerometry data, and then model its relationship between MetS risk factors with nonlinear seemingly unrelated regressions, incorporating dependence among MetS risk factors. The novel features of this model give the medical research community a new way to understand relationships between MVPA and MetS. The results of this approach present the field with a different modeling perspective than previously taken and suggest future avenues of scientific discovery.

Assessing adult physical activity and compliance with 2008 CDC guidelines using a Bayesian two-part measurement error model.

While there is wide agreement that physical activity is an important component of a healthy lifestyle, it is unclear how many people adhere to public health recommendations on physical activity. The Physical Activity Guidelines (PAG), published by the CDC, provides guidelines to American adults, but it is difficult to assess compliance with these guidelines. The PAG further complicates adherence assessment by recommending activity to occur in at least 10 min bouts. To better understand the measurement capabilities of various instruments to quantify activity, and to propose an approach to evaluate activity relative to the PAG, researchers at Iowa State University administered the Physical Activity Measurement Survey (PAMS) to over 1000 participants in four different Iowa counties. In this paper, we develop a two-part Bayesian measurement error model and apply it to the PAMS data in order to assess compliance with the PAG in the Iowa adult population. The model accurately accounts for the 10 min bout requirement put forth in the PAG. The measurement error model corrects biased estimates and accounts for day-to-day variation in activity. The model is also applied to the nationally representative National Health and Nutrition Examination Survey.

Comparison and calibration of 24-hour physical activity recall in adult population.

AbstractThis study compared and calibrated metabolic equivalents (METs) per day from 24-hour physical activity recall (24hPAR) with accelerometry. A sub-sample of 74 adults of both sexes, residents of Brasília, Brazil, from a larger study had same day measurements of accelerometry and 24hPAR data. METs values were assessed by accelerometry (7 consecutive days of use) and by 24hPAR (minimum of one and maximum of 2 per person). A script was written in the R statistical software to analyse the recall and accelerometer data. The script ran a simple linear regression to visualize the relationship between total METs/day for the two methods and to execute the recall measurement error correction. Most of participants were female (54.1%), with at least university graduate (94.6%) and mean age of 34.8 years (±11.83). The correlation coefficient obtained between 24hPAR and accelerometer was r = 0.55, considered moderate and significant (p < 0.001). A majority of the participants (77%) underestimated METs values compared to accelerometry when answering the questionnaire. Calibration of 24hPAR allowed us to approximate MET values to the accelerometer. The calibration equation to correct total METs/day for measurement error is (total 24hPAR METs/day - 10.6)/0.619. The 24hPAR is a decent tool to assess PA level in large adults' samples. However, compared with accelerometer, it underestimates METs values, which can be corrected with the use of the calibration equation provided in this study.

Pharmacokinetics of bempedoic acid in patients with renal impairment.

Bempedoic acid is an ATP citrate lyase inhibitor approved for the treatment of hypercholesterolemia. The objective of this phase I study was to assess the pharmacokinetics (PKs) and safety of bempedoic acid in 24 subjects with normal renal function or mild, moderate, or severe renal impairment. All subjects received a single oral bempedoic acid 180-mg dose and PK parameters were monitored for up to 23 days. Resulting estimates of area under the concentration-time curve exposure following bempedoic acid treatment were 1.5-fold, 2.2-fold, and 2.2-fold higher in subjects with mild, moderate, or severe renal impairment, respectively, compared with subjects with normal renal function. With decreases in renal function, plasma free fraction was increased up to 20.1%, whereas total and unbound clearances were decreased by 55.2% and 62.6%, respectively, in subjects with severe renal impairment relative to those with normal renal function. These observed decreases in total and unbound oral clearance in subjects with decreased renal function are not explained by the increases in free fraction and might therefore also be attributable to changes in bioavailability or intrinsic clearance. Bempedoic acid was generally well-tolerated and the incidence and type of adverse events were not affected by the degree of renal impairment. In conclusion, bempedoic acid exposures in subjects with renal impairment were increased up to approximately two-fold with no safety signals identified, consistent with findings in phase III patients with mild or moderate renal impairment. No dose adjustments are necessary for patients with mild or moderate renal impairment.

NaPi-IIb Inhibition for Hyperphosphatemia in CKD Hemodialysis Patients.

INTRODUCTION: Chronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD. METHODS: Part A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring. RESULTS: Six patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was -2.2±1.5 mg/dl versus -1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups. CONCLUSIONS: DS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.

Modeling energy balance while correcting for measurement error via free knot splines.

Measurements of energy balance components (energy intake, energy expenditure, changes in energy stores) are often plagued with measurement error. Doubly-labeled water can measure energy intake (EI) with negligible error, but is expensive and cumbersome. An alternative approach that is gaining popularity is to use the energy balance principle, by measuring energy expenditure (EE) and change in energy stores (ES) and then back-calculate EI. Gold standard methods for EE and ES exist and are known to give accurate measurements, albeit at a high cost. We propose a joint statistical model to assess the measurement error in cheaper, non-intrusive measures of EE and ES. We let the unknown true EE and ES for individuals be latent variables, and model them using a bivariate distribution. We try both a bivariate Normal as well as a Dirichlet Process Mixture Model, and compare the results via simulation. Our approach, is the first to account for the dependencies that exist in individuals' daily EE and ES. We employ semiparametric regression with free knot splines for measurements with error, and linear components for error free covariates. We adopt a Bayesian approach to estimation and inference and use Reversible Jump Markov Chain Monte Carlo to generate draws from the posterior distribution. Based on the semiparameteric regression, we develop a calibration equation that adjusts a cheaper, less reliable estimate, closer to the true value. Along with this calibrated value, our method also gives credible intervals to assess uncertainty. A simulation study shows our calibration helps produce a more accurate estimate. Our approach compares favorably in terms of prediction to other commonly used models.

Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease.

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.

Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function.

This phase I, open-label, single-dose study evaluated the pharmacokinetics, safety, and tolerability of renally excreted drug dexpramipexole in subjects with normal and impaired renal function, i.e. mild, moderate, severe renal impairment, or end-stage renal disease (ESRD) requiring hemodialysis when matched by age and sex. Dexpramipexole area under the curves (AUCs), but not Cmax , were significantly increased with the severity of renal impairment after a single dose administration. The geometric mean ratio of dose-normalized AUC(0-72) was 1.4, 1.7, 2.7, and 4.5, respectively, in mild, moderate, severe renal impairment, and ESRD subjects when compared to healthy subjects. There was a strong association between renal function (eGFR) and dexpramipexole CLr. The slope (90% confidence interval(CI)) of eGFR and renal clearance (CLr) in the regression model was 3.1 (2.4, 3.7). Dexpramipexole elimination in ESRD subjects during both dialysis and non-dialysis (i.e., interval between dialysis) was insignificant. Single 75 mg and 150 mg doses of dexpramipexole were well tolerated, and the safety profile was comparable across renal function groups. Extensive drug accumulation may occur with repeated dosing in patients with significant renal impairment. It is recommended that dexpramipexole not to be given to patients with severe renal impairment or in those with ESRD.