High Within-subject Variability Research Articles

Curved non-motorized treadmills do not biomechanically replicate overground running better than motorized treadmills

ABSTRACT The purpose of this study was to determine if curved non-motorized treadmills can reproduce overground running better than motorized treadmills by analysing the differences in joint kinematics (hip, knee, and ankle) using SPM. Nineteen recreational runners completed three randomized running tests on these surfaces. Kinematic data from the hip, knee, and ankle joints were collected. Two-tailed SPM t-tests were performed to analyse time-continuous gait cycles in three anatomical planes of each joint. Higher within-subject variability was observed in the frontal and transverse planes during curved non-motorized treadmill running. SPM analysis showed more significant differences (p < 0.05) between curved non-motorized treadmill and overground than between motorized treadmill and overground, mainly in knee (from 12% to 30% and 93% to 99% of the gait cycle) and ankle (from 19% to 23% of the gait cycle) in the sagittal plane. Therefore, running on curved non-motorized treadmills is more biomechanically different compared to overground than motorized treadmills, and might not be the best strategy to replicate overground running in terms of joint kinematics during highly controlled research studies. However, they could be an interesting tool in rehabilitation or training environments since the changes observed in joint kinematics were likely not functionally relevant.

Physiological Dynamics in the Upper Gastrointestinal Tract and the Development of Gastrointestinal Absorption Models for the Immediate-Release Oral Dosage Forms in Healthy Adult Human.

This review is a revisit of various oral drug absorption models developed in the past decades, focusing on how to incorporate the physiological dynamics in the upper gastrointestinal (GI) tract. For immediate-release oral drugs, GI absorption is a critical input of drug exposure and subsequent human body response, yet difficult to model largely due to the complex GI environment. One of the biggest hurdles lies at capturing the high within-subject variability (WSV) of bioavailability measures, which can be mechanistically explained by the GI physiological dynamics. A thorough summary of how GI dynamics is handled in the absorption models would promote the development of mechanism-based oral drug absorption models, aid in the design of clinical studies regarding dosing regimens and bioequivalence studies based on WSV, and advance the decision-making on formulation selection.

Monitoring abnormal nocturnal behaviour in the homes of patients living with dementia.

People living with dementia (PLWD) often exhibit marked sleep disturbances. These cause substantial care challenges and may be causally related to dementia progression. Collecting ecologically valid data on sleep disturbance in naturalistic settings has been difficult. As a result, sleep assessments in PLWD are generally limited to short studies in sleep laboratories or data collection from wearables, where compliance is problematic. Here, we demonstrate how passive internet of things (IoT) sensors can be used to monitor the effects of dementia on nocturnal behaviour and physiology. Using the Withings under-mattress pressure sensor, we validated bed occupancy and physiological measures in 35 older adults tested both at home and in the laboratory. We then examined data collected between 2019 and 2021 from the general population (N=13,663) and from a cohort of PLWD taking part in the UK DRI study of home monitoring for PLWD (N=46). More than 4 million unique bed mat observations were analysed. Arise time across all subjects was negatively correlated with time to bed (Fig.1a, r(13,617) =-0.5, p<.0001). Bed occupancy increased with age, but PLWD spent more time in bed than age-matched controls (Fig.1b) and had more nocturnal awakenings (Fig.1c). Explainable gradient boosting machine learning was successfully used to classify data from individual nights (PLWD vs. general population). PLWD probability was related to specific changes, such as increased awakenings, high or low time spent in bed, high heart rate and low breathing rate (Fig.2). We also explored variations in night-time behaviour and physiology over time for individual PLWD (Fig.3a). High within-subject variability was present, which related to disease progression, intercurrent illness and changes in medication. Data from each night was transformed into a risk score for each metric (Fig.3b) and a compound risk score. These quantify the risk of abnormal night-time behaviour and physiology produced by dementia (Fig.3c) and reflect clinically relevant changes in PLWD. Taken together our work demonstrates how digital biomarkers collected passively using under mattress technology can be used to automatically monitor the nocturnal effects of dementia across large populations. The approach is also potentially applicable for preclinical screening and the evaluation of treatments effects.

Modeling the expenditure and reconstitution of distance above critical speed during two swimming interval training sessions.

In swimming, the speed-time relationship provides the critical speed (CS) and the maximum distance that can be performed above CS (D′). During intermittent severe intensity exercise, a complete D′ depletion coincides with task failure, while a sub-CS intensity is required for D′ reconstitution. Therefore, determining the balance D′ remaining at any time during intermittent exercise (D'BAL) could improve training prescription. This study aimed to 1) test the D'BAL model for swimming; 2) determine an equation to estimate the time constant of the reconstitution of D' (τD′); and 3) verify if τD′ is constant during two interval training sessions with the same work intensity and duration and recovery intensity, but different recovery duration. Thirteen swimmers determined CS and D′ and performed two high-intensity interval sessions at a constant speed, with repetitions fixed at 50 m. The duration of passive recovery was based on the work/relief ratio of 2:1 (T2:1) and 4:1 (T4:1). There was a high variability between sessions for τD' (coefficient of variation of 306%). When τD′ determined for T2:1 was applied in T4:1 and vice versa, the D'BAL model was inconsistent to predict the time to exhaustion (coefficient of variation of 29 and 28%). No linear or nonlinear relationships were found between τD′ and CS, possibly due to the high within-subject variability of τD'. These findings suggest that τD′ is not constant during two high-intensity interval sessions with the same recovery intensity. Therefore, the current D'BAL model was inconsistent to track D′ responses for swimming sessions tested herein.

Pharmacokinetic Comparison of Chitosan-Derived and Biofermentation-Derived Glucosamine in Nutritional Supplement for Bone Health.

Glucosamine and chondroitin sulfate have been used as nutritional supplementation for joint tissues and osteoarthritis (OA). Biofermented glucosamine is of great interest in the supplement industry as an alternative source of glucosamine. The purpose of this study is to compare the pharmacokinetics of chitosan-derived glucosamine and biofermentation-derived glucosamine as nutritional supplementation. In a randomized, double-blind and cross-over study design, we recruited subjects of healthy men and women. The pharmacokinetics of glucosamine were examined after a single dose of glucosamine sulfate 2KCl (1500 mg) with two different sources of glucosamine (chitosan-derived glucosamine and biofermentation-derived glucosamine) to male and female subjects fitted with intravenous (iv) catheters for repeated blood sampling up to 8 h. According to plasma concentration–time curve of glucosamine after an oral administration of 1500 mg of glucosamine sulfate 2KCl, AUC0–8h and AUC0–∞ values of glucosamine following oral administration of chitosan-derived and biofermentation-derived glucosamine formulations were within the bioequivalence criteria (90% CI of ratios are within 0.8–1.25). The mean Cmax ratios for these two formulations (90% CI of 0.892–1.342) did not meet bioequivalence criteria due to high within-subject variability. There were no statistically significant effects of sequence, period, origin of glucosamine on pharmacokinetic parameters of glucosamine such as AUC0–8h, AUC0–∞, Cmax. Our findings suggest that biofermentation-derived glucosamine could be a sustainable source of raw materials for glucosamine supplement.

Pregnancy Exposure to Phenols and Anthropometric Measures in Gestation and at Birth.

Some synthetic phenols alter pathways involved in fetal development. Despite their high within-subject temporal variability, earlier studies relied on spot urine samples to assess pregnancy exposure. In this study, we examined associations between prenatal phenol exposure and fetal growth. We measured concentrations of two bisphenols, four parabens, benzophenone-3, and triclosan in 478 pregnant women in two weekly pools of 21 samples each, collected at 18 and 34 gestational weeks. We used adjusted linear regressions to study associations between phenol concentrations and growth outcomes assessed twice during pregnancy and at birth. Benzophenone-3 was positively associated with all ultrasound growth parameters in at least one time point, in males but not females. In females, butylparaben was negatively associated with third-trimester abdominal circumference and weight at birth. We observed isolated associations for triclosan (negative) and for methylparaben and bisphenol S (positive) and late pregnancy fetal growth. Our results suggest associations between prenatal exposure to phenols and fetal growth. Benzophenone-3 was the exposure most consistently (positively) associated across all growth parameters.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.

Associations between a mixture of phenols and phthalates and child behaviour in a French mother-child cohort with repeated assessment of exposure.

Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median=21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother-child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5-5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95%CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95%CI: -0.42, 3.81) and 1.17 points (95%CI: -0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.

Comparison of strategies to efficiently combine repeated urine samples in biomarker-based studies

BackgroundIn biomarker-based studies, collecting repeated biospecimens per participant can decrease measurement error, particularly for biomarkers displaying high within-subject variability. Guidelines to combine such repeated biospecimens do not exist. AimsTo compare the efficiency of several designs relying on repeated biospecimens to estimate exposure over 7 days. MethodsWe quantified triclosan and bisphenol A (BPA) in all urine voids (N = 427) collected over seven days from eight individuals. We estimated the volume-weighted concentrations for all urine samples collected during a week and compared these gold standards with the concentrations obtained for equal-volume pools (standardized or not for urine dilution), unequal-volume pools (based on sample volume or creatinine concentration), and for the mean of the creatinine-standardized concentrations measured in each spot sample. ResultsFor both chemicals, correlations with gold standards were similar for equal- and unequal-volume pooling designs. Only for BPA, correlation coefficients were markedly lower after standardization for specific gravity or creatinine of concentrations estimated in equal-volume pools. Averaging BPA creatinine-standardized concentrations measured in each spot sample led also to lower correlations with gold standards compared to those obtained for unstandardized pooling designs. ConclusionFor BPA and triclosan, considering individual urine sample volume or creatinine concentrations when pooling is unnecessary because equal-volume pool adequately estimates concentrations in gold standards. Standardization for specific gravity or creatinine of the concentrations assessed in equal-volume pool as well as averaging creatinine-standardized concentrations measured in each individual spot sample are not suitable for BPA. These results provide a practical framework on how to combine repeated biospecimens in epidemiological studies.

Prenatal Exposure to Endocrine-Disrupting Chemicals and Asthma and Allergic Diseases.

Endocrine-disrupting chemicals (EDCs) interfere with endogenous hormones and are present in many consumer products. In addition, they affect the development and functions of the immune system. The prenatal period is critical, because exposure to EDCs can induce irreversible changes in the immune system and increase susceptibility to asthma and allergies later in life. Nonpersistent EDCs are of most concern owing to their high annual production and potential toxicity. In this review, we summarize the literature on the effects of prenatal exposure to nonpersistent EDCs-phthalates and phenols-on asthma and allergic diseases, describe the underlying biological mechanisms, and make recommendations. Between 2011 and 2020, a total of 19 prospective studies were published. Most of these were focused on phthalates and bisphenol A and few on other bisphenols, parabens, triclosan, and benzophenone-3. Evidence remains insufficient owing to differences in chemical use between countries, sociodemographic characteristics of the study populations, misclassification of exposure due to the high within-subject variability, and heterogeneity in the definition of health outcomes. EDCs can alter airway cell differentiation and gut microbiota, shift the immune response towards TH2, alter expression of T regulatory cells and TH17, and weaken innate immunity. In order to better understand the burden of EDCs on the respiratory and immune systems, we require thoughtfully designed studies to assess exposure, appropriately characterize asthma and allergic phenotypes, and evaluate biological mechanisms and EDC mixtures.

Monitoring diaphragm function in the ICU.

To review the clinical problem of diaphragm function in critically ill patients and describes recent advances in bedside monitoring of diaphragm function. Diaphragm weakness, a consequence of diaphragm dysfunction and atrophy, is common in the ICU and associated with serious clinical consequences. The use of ultrasound to assess diaphragm structure (thickness, thickening) and mobility (caudal displacement) appears to be feasible and reproducible, but no large-scale 'real-life' study is available. Diaphragm ultrasound can also be used to evaluate diaphragm muscle stiffness by means of shear-wave elastography and strain by means of speckle tracking, both of which are correlated with diaphragm function in healthy. Electrical activity of the diaphragm is correlated with diaphragm function during brief airway occlusion, but the repeatability of these measurements exhibits high within-subject variability. Mechanical ventilation is involved in the pathogenesis of diaphragm dysfunction, which is associated with severe adverse events. Although ultrasound and diaphragm electrical activity could facilitate monitoring of diaphragm function to deliver diaphragm-protective ventilation, no guidelines concerning the use of these modalities have yet been published. The weaning process, assessment of patient-ventilator synchrony and evaluation of diaphragm function may be the most clinically relevant indications for these techniques.

Variability of Seminal Plasma Cadmium Concentrations and Its Associations with Semen Quality among Healthy Chinese Men Screened as Potential Sperm Donors

TPS 631: Metals and health 1, Johan Friso Foyer, Floor 1, August 27, 2019, 3:00 PM - 4:30 PM Background: Cadmium (Cd) is a well-documented toxic metal, which has demonstrated adverse effects on male semen quality in animal studies. However, the results from human studies are inconsistent, probably due to the high within-subject variability in measurements of Cd in biological specimens and semen quality parameters. Objectives: To characterize the variability of Cd concentrations in seminal plasma and assessed its associations with repeated measurements of semen quality among healthy men who came to the Hubei Province Human Sperm Bank for donations screening. Methods: The reproducibility of Cd concentrations in 232 seminal plasma samples collected from 93 men was assessed using the intraclass correlation coefficient (ICC). The associations of Cd in within-subject pooled seminal plasma (n=1156) with repeated measurements of semen quality parameters (n = 5619) were assessed using linear mixed models with an individual-specific random intercept. Semen analyses were conducted by qualified laboratory technologists following the guidelines of the World Health Organization, and Cd concentration was determined by inductively coupled plasma-mass spectrometry. Results: Cd was detected in > 85% of the seminal plasma specimens. Fair to good reproducibility (ICC = 0.71) was achieved for serial measurements of Cd. Compared with men in the lowest Cd quartile, men in the highest quartile of Cd had a reduced semen volume and total motility of 3.25% (95% CI: -6.29%, -0.20%; p for trend = 0.027) and -1.88% (95% CI: -3.82%, 0.10%; p for trend = 0.083), respectively. Similar results were achieved when modeling Cd concentration (log-transformed) as a continuous variable in cubic spline models. Conclusion: Cd in seminal plasma were relatively stable. Exposure to high Cd may adversely affect semen volume and motility. Future studies in a larger and general population are needed to verify our findings.

Correlation of EEG spectra, connectivity, and information theoretical biomarkers with psychological states in the epilepsy monitoring unit — A pilot study

At the level of individual experience, the relation between electroencephalographic (EEG) phenomena and subjective ratings of psychological states is poorly examined. This study investigated the correlation of quantitative EEG markers with systematic high-frequency monitoring of psychological states in patients admitted to the epilepsy monitoring unit (EMU).We used a digital questionnaire, including eight standardized items about stress, energy level, mood, ward atmosphere, seizure likelihood, hopefulness/frustration, boredom, and self-efficacy. Self-assessments were collected four times per day, in total 15 times during the stay in the EMU. We extracted brainrate, Hjorth parameters, Hurst exponent, Wackermann parameters, and power spectral density from the EEG. We performed correlation between these quantitative EEG measures and responses to the 8 items and evaluated their significance on single subject and on group level.Twenty-one consecutive patients (12 women/9 men, median age: 29 years, range: 18–74 years) were recruited. On group level, no significant correlations were found whereas on single-subject level, we found significant correlations for 6 out of 21 patients. Most significant correlations were found between Hjorth parameters and items that reflect changes in mood or stress.This study supports the feasibility of correlating quantitative EEG measures with psychological states in routine EMU settings and emphasizes the need for single-subject statistics when assessing aspects with high interindividual variance. Future studies should select samples with high within-subject variability of psychological states and examine a subsample with patients encountering a critical number of seizures needed in order to relate the psychological states to the ultimate question: Are psychological states potential indicators for seizure likelihood?

Portable Sensors Add Reliable Kinematic Measures to the Assessment of Upper Extremity Function.

Ordinal scales with low resolution are used to assess arm function in clinic. These scales may be improved by adding objective kinematic measures. The aim was to analyze within-subject, inter-rater and overall reliability (i.e., including within-subject and inter-rater reliability) and check the system’s validity of kinematic measures from inertial sensors for two such protocols on one person. Twenty healthy volunteers repeatedly performed two tasks, finger-to-nose and drinking, during two test sessions with two different raters. Five inertial sensors, on the forearms, upper arms and xiphoid process were used. Comparisons against an optical camera system evaluated the measurement validity. Cycle time, range of motion (ROM) in shoulder and elbow were calculated. Bland–Altman plots and linear mixed models including the generalizability (G) coefficient evaluated the reliability of the measures. Within-subject reliability was good to excellent in both tests (G = 0.80–0.97) and may serve as a baseline when assessing upper extremities in future patient groups. Overall reliability was acceptable to excellent (G = 0.77–0.94) for all parameters except elbow axial rotation in finger-to-nose task and both elbow axial rotation and flexion/extension in drinking task, mainly due to poor inter-rater reliability in these parameters. The low to good reliability for elbow ROM probably relates to high within-subject variability. The sensors provided good to excellent measures of cycle time and shoulder ROM in non-disabled individuals and thus have the potential to improve today’s assessment of arm function.

Urinary levels of bisphenol A, F and S and markers of oxidative stress among healthy adult men: Variability and association analysis

BackgroundBisphenol F (BPF) and bisphenol S (BPS) are increasingly used as alternatives to endocrine disrupting chemical bisphenol A (BPA). Evidence from in vitro and animal studies demonstrates that BPA, BPF and BPS induce oxidative stress, a proposed mechanism that is relevant to various adverse health effects. Evaluation in humans is hampered by the potentially high within-subject variability of urinary measurements. ObjectiveTo evaluate the variability and associations of levels of BPA, BPS, BPF and 3 oxidative stress markers [i.e., 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in urine collected on multiple occasions over 3 months. MethodA total of 529 spot urine samples, including 88 first morning voids (FMVs) and 24-h specimens, were gathered from 11 adult men on days 0, 1, 2, 3, 4, 30, 60 and 90 and analyzed for BPA, BPF, BPS, 8-OHdG, 8-isoPGF2α and HNE-MA. Intraclass correlation coefficients (ICCs) were estimated to characterize the reproducibility of urinary bisphenols and oxidative stress markers, and linear mixed models were applied to assess the associations between markers of exposure and response. ResultsBPA and BPF were detected in ≥85% of the spot samples, while BPS in 13% of the samples. High degrees of within-subject variability were found for BPA, BPF, 8-OHdG, 8-isoPGF2α and HNE-MA in spot samples, FMVs and 24-h specimens (creatinine-corrected ICCs ≤ 0.37). The sensitivities were low-to-moderate (0.30–0.63) when using single spot samples or FMVs to predict high (>27th, or 36th percentile) 3-month average urinary levels of BPA, BPF, 8-OHdG, 8-isoPGF2α and HNE-MA. Collecting repeated specimens at different time points improved the accuracy of classification for markers of exposure and response. Elevated urinary BPA and BPF were associated with significantly higher levels of oxidative stress markers. ConclusionsRepeated urinary specimens are required to characterize bisphenol exposure levels and the oxidative stress status of individuals. Exposure to BPA and BPF may partly contribute to the elevated urinary levels of oxidative stress makers in adult men.

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5‐day repeated sessions study

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a "build-up" effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day-to-day was low in both groups, implying high within-subject variability of both active and sham iTBS after-effects. In contrast, we found a high within-subject repeatability of resting and active motor threshold, and baseline motor-evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.

The many ways sputum flows – Dealing with high within-subject variability in cystic fibrosis sputum rheology

We evaluated test-retest reliability of sputum viscoelastic properties in clinically stable patients with cystic fibrosis (CF). Data from a prospective, randomized crossover study was used to determine within-subject variability of sputum viscoelasticity (G’, storage modulus and G”, loss modulus at 1 and 10 rad s−1) and solids content over three consecutive visits. Precision of sputum properties was quantified by within-subject standard deviation (SDws), coefficient of variation (CV) and intraclass correlation coefficients (ICC). Fifteen clinically stable adults with CF (FEV1 range 24–94% predicted) were included. No differences between study visits (mean ± SD 8 ± 2 days) were observed for any sputum rheology measure. CV’s for G’, G” and solids content ranged between 40.3–45.3% and ICC’s between 0.21–0.42 indicating poor to fair test-retest reliability. Short-term within-subject variability of sputum properties is high in clinically stable adults with CF. Investigators applying shear rheology experiments in future prospective studies should consider using multiple measurements aiming to increase precision of sputum rheological outcomes.

Trunk-lower limb coordination pattern during gait in patients with ataxia

ObjectiveAlthough deficit of coordination between the upper and lower body segments might play an important role in impairing gait and stability in ataxic patients, this deficit has not been investigated in subjects with ataxia so far. To evaluate the coordination between trunk and thigh in a sample of patients with ataxia compared with healthy controls and to correlate the coordination measures with the clinical severity. DesignProspective observational study. SubjectsSixteen patients with degenerative cerebellar ataxia and sixteen age- and sex-matched controls were studied. MethodsWe assessed the coordination on the sagittal plane between trunk and thigh, considered as rigid segments, by the continuous relative phase (CRP) method. We used the coefficient of multiple correlation (CMC) to measure the within-subject (CMCWS) variability, and the SARA scale to assess clinical severity. ResultsCRP curves are dissimilar between ataxic patients and controls, the former showing a chaotic behavior compared to the well-shaped CRP curves observed in the latter. Trunk-thigh coordination has a higher within-subject variability in ataxic patients (median CMCWS: 0.53 for patients, 0.89 for controls, p<0.001). We also found that the CMCWS of the CRP curves negatively correlates with the gait (ρ: −0.565, p: 0.023) and stance (ρ: −0.567, p: 0.022) sub-scores and the total score of the SARA scale (ρ: −0.711, p: 0.002). ConclusionsAtaxia shows a deficit of spatio-temporal coordination between trunk and thigh. Such a deficit is correlated with the degree of the clinical impairment indicating an important role of inter-segmental coordination in determining the severity of ataxia.

Associations between urinary diphenyl phosphate and thyroid function

Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer with widespread human exposure. Data on health effects of TPHP are limited. Recent toxicological studies suggest TPHP may alter thyroid function. We used repeated measures to assess the temporal variability in urinary concentrations of the TPHP metabolite, diphenyl phosphate (DPHP), and to examine relationships between DPHP concentrations and thyroid hormones. We sampled 51 adults at months 1, 6, and 12 from 2010 to 2011. Urine samples were analyzed for DPHP. Serum samples were analyzed for free and total thyroxine (fT4, TT4), total triiodothyronine (TT3), and thyroid stimulating hormone (TSH). We assessed variability in DPHP using intraclass correlation coefficients (ICCs) and kappa statistics. We used linear mixed-effects models to examine associations between DPHP and thyroid hormones. DPHP was detected in 95% of urine samples. Mean DPHP concentrations were 43% higher in women than men. DPHP showed high within-subject variability (ICC range, 0.13–0.39; kappa range, 0.16–0.39). High versus low (≥2.65 vs. <2.65ng/mL) DPHP in all participants was associated with a 0.43μg/dL (95% confidence interval: 0.15, 0.72) increase in mean TT4 levels. In sex-stratified analyses, high versus low DPHP was associated with a 0.91μg/dL (95% CI: 0.47, 1.36) increase in mean TT4 in women. The association was attenuated in men (βeta=0.19; 95% CI: −0.15, 0.52). We found no significant associations between DPHP and fT4, TT3, or TSH. We found evidence that TPHP exposure may be associated with increased TT4 levels, especially in women.

Within-subject Pooling of Biological Samples to Reduce Exposure Misclassification in Biomarker-based Studies.

For chemicals with high within-subject temporal variability, assessing exposure biomarkers in a spot biospecimen poorly estimates average levels over long periods. The objective is to characterize the ability of within-subject pooling of biospecimens to reduce bias due to exposure misclassification when within-subject variability in biomarker concentrations is high. We considered chemicals with intraclass correlation coefficients of 0.6 and 0.2. In a simulation study, we hypothesized that the chemical urinary concentrations averaged over a given time period were associated with a health outcome and estimated the bias of studies assessing exposure that collected 1 to 50 random biospecimens per subject. We assumed a classical type error. We studied associations using a within-subject pooling approach and two measurement error models (simulation extrapolation and regression calibration), the latter requiring the assay of more than one biospecimen per subject. For both continuous and binary outcomes, using one sample led to attenuation bias of 40% and 80% for compounds with intraclass correlation coefficients of 0.6 and 0.2, respectively. For a compound with an intraclass correlation coefficient of 0.6, the numbers of biospecimens required to limit bias to less than 10% were 6, 2, and 2 biospecimens with the pooling, simulation extrapolation, and regression calibration methods (these values were, respectively, 35, 8, and 2 for a compound with an intraclass correlation coefficient of 0.2). Compared with pooling, these methods did not improve power. Within-subject pooling limits attenuation bias without increasing assay costs. Simulation extrapolation and regression calibration further limit bias, compared with the pooling approach, but increase assay costs.