Between-subject Variability Research Articles

Physical activity and aging research: opportunities abound.

Aging is associated with large between-subjects variability in motor function among older adults, which can compromise identifying the mechanisms for age-related reductions in motor performance. This variability is in part explained by differences among older adults in habitual physical activity. Quantifying and accounting for physical activity levels of the participants in aging studies will help differentiate those changes in motor function associated with biological aging rather than those induced by inactivity. Novelty: Quantification of physical activity levels in studies with older participants will help differentiate the effects of aging rather than physical inactivity.

Changes in glucocorticoid receptor sensitivity following long‐term ethanol self‐administration in male and female rhesus macaques

Stress can alter ethanol consumption and long-term use results in adaptation of the stress response, highlighting a bidirectional relationship that remains poorly understood. Non-human primates are an excellent model to investigate the interaction of stress and long-term ethanol use due to their similar neuroendocrine system to humans and propensity to chronically drink intoxicating amounts of alcohol. Here, circulating stress hormones (adrenocorticotropin hormone (ACTH) and cortisol) were measured in response to a low (17 mg/kg) and high (130 mg/kg) dose of dexamethasone, a potent glucocorticoid receptor (GR) agonist. The dexamethasone response was compared before (baseline) and after 7 months of daily 22 h/d ethanol self-administration in young adult male (n=6) and female (n=6) rhesus macaques. At both timepoints, the high dose dexamethasone challenge resulted in 90-100% suppression of both ACTH and cortisol with no difference between sexes. At baseline, low dose dexamethasone reduced both ACTH and cortisol, but to a lesser degree and with greater between-subject variability, 0 – 60%. Following seven-months of daily ethanol consumption (average intakes ranging from 0.6 – 4.0 g/kg/day) the response to low dose dexamethasone was greater. This effect was more robust in females compared to males. Additionally, the change in suppression between baseline and following long-term daily ethanol consumption correlated with daily intake, such that the magnitude of change over time was greater in heavier drinkers. Because stress increases reliance on putamen-dependent or habitual behavior and heavy ethanol drinking leads to excitatory-inhibitory neurotransmission imbalance within the putamen, we tested the hypothesis that long-term ethanol self-administration will alter striatal transmission via the GR. Therefore, we used whole cell patch clamp electrophysiology to investigate the effect of bath application of dexamethasone onto putamen medium spiny neurons (MSNs). Dexamethasone rapidly decreased the area and amplitude of spontaneous inhibitory postsynaptic currents among binge drinkers. These data show that acute dexamethasone, presumably via activation of the membrane bound GR, activated fewer GABAergic receptors among binge drinkers. These data highlight a unique role of the GR within the putamen that may mediate stress dependent changes contributing to addiction vulnerability, particularly among binge drinkers.

Single-Trial Kernel-Based Functional Connectivity for Enhanced Feature Extraction in Motor-Related Tasks

Motor learning is associated with functional brain plasticity, involving specific functional connectivity changes in the neural networks. However, the degree of learning new motor skills varies among individuals, which is mainly due to the between-subject variability in brain structure and function captured by electroencephalographic (EEG) recordings. Here, we propose a kernel-based functional connectivity measure to deal with inter/intra-subject variability in motor-related tasks. To this end, from spatio-temporal-frequency patterns, we extract the functional connectivity between EEG channels through their Gaussian kernel cross-spectral distribution. Further, we optimize the spectral combination weights within a sparse-based -norm feature selection framework matching the motor-related labels that perform the dimensionality reduction of the extracted connectivity features. From the validation results in three databases with motor imagery and motor execution tasks, we conclude that the single-trial Gaussian functional connectivity measure provides very competitive classifier performance values, being less affected by feature extraction parameters, like the sliding time window, and avoiding the use of prior linear spatial filtering. We also provide interpretability for the clustered functional connectivity patterns and hypothesize that the proposed kernel-based metric is promising for evaluating motor skills.

Modeling Between-Subject Variability in Subcutaneous Absorption of a Fast-Acting Insulin Analogue by a Nonlinear Mixed Effects Approach.

Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective dosing and timing of the administration process. In this work, we present a nonlinear mixed effects model describing the between-subject variability observed in the subcutaneous absorption of fast-acting insulin. A set of 14 different models was identified on a large and frequently-sampled database of lispro pharmacokinetic data, collected from 116 subjects with type 1 diabetes. The tested models were compared, and the best one was selected on the basis of the ability to fit the data, the precision of the estimated parameters, and parsimony criteria. The selected model was able to accurately describe the typical trend of plasma insulin kinetics, as well as the between-subject variability present in the absorption process, which was found to be related to the subject’s body mass index. The model provided a deeper understanding of the insulin absorption process and can be incorporated into simulation platforms to test and develop new open- and closed-loop treatment strategies, allowing a step forward toward personalized insulin therapy.

Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody.

The thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modelling aims at describing and explaining the experimentally observed important variability of the TG curves between subjects and the individual effects of spiking with a TFPI antibody. The models consist of an empirical description of the TG kinetics, accounting for an additive residual error and between-subject variability on its parameters. Factor VIII and TFPI were found to significantly explain and reduce the variability of the TG of haemophilia A samples. Besides, the model is shown to correctly reproduce the variability in the response to the ex vivo spiking with the TFPI antibody, by combining the empirical description of TG to a simple Hill equation that accounts for the binding between TFPI and different doses of its antibody. Such models can be useful for clinical practice, with the analysis and comparison of the distributions of TG profiles in healthy and haemophilia populations; and also for research, with the analysis of the effect of TFPI and its neutralization on individual TG profiles.

Population pharmacokinetics of Pseudechis porphyriacus (red-bellied black snake) venom in snakebite patients

Objectives Understanding the time course of venom exposure in snakebite patients is important for the optimisation of treatment including antivenom dose and timing. We aimed to investigate the pharmacokinetics of red-bellied black snake (RBBS; Pseudechis porphyriacus) venom in envenomed patients. Methods Timed venom concentration data were obtained from patients with RBBS envenomation recruited to the Australian Snakebite Project (ASP), including demographics and antivenom treatment. Venom concentrations were measured using an enzyme immunoassay. Data were modelled using NONMEM version 7.3. Uncertainty in venom “dose” was accounted for by arbitrarily fixing the average amount to 1 mg and incorporating between-subject variability on relative bioavailability. A scale parameter for venom clearance was implemented to account for the rapid venom clearance following antivenom dosing. A sensitivity analysis was performed to determine the magnitude of venom clearance amplification. Results There were 457 venom concentrations in 114 patients (median age 41, 2–90 y; 80 male). Antivenom was administered to 54 patients a median of 4.2 h post-bite (0.67 to 32 h). A one-compartment model with first-order absorption and elimination provided the best description of the data. The estimated clearance and volume of distribution were 5.21 L/h and 39.9 L, respectively. The calculated elimination half-life of P. porphyriacus venom from the final pharmacokinetic model was 5.35 ± 0.36 h. The variability in the relative dose of injected venom was 140%. Antivenom administration increased venom clearance by 40-fold. Ten patients showed evidence of a double peak in the absorption profile. Conclusion The information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom.

Individual variation underlying brain age estimates in typical development

Typical brain development follows a protracted trajectory throughout childhood and adolescence. Deviations from typical growth trajectories have been implicated in neurodevelopmental and psychiatric disorders. Recently, the use of machine learning algorithms to model age as a function of structural or functional brain properties has been used to examine advanced or delayed brain maturation in healthy and clinical populations. Termed ‘brain age’, this approach often relies on complex, nonlinear models that can be difficult to interpret. In this study, we use model explanation methods to examine the cortical features that contribute to brain age modelling on an individual basis.In a large cohort of n = 768 typically-developing children (aged 3–21 years), we build models of brain development using three different machine learning approaches. We employ SHAP, a model-agnostic technique to identify sample-specific feature importance, to identify regional cortical metrics that explain errors in brain age prediction. We find that, on average, brain age prediction and the cortical features that explain model predictions are consistent across model types and reflect previously reported patterns of regions brain development. However, while several regions are found to contribute to brain age prediction error, we find little spatial correspondence between individual estimates of feature importance, even when matched for age, sex and brain age prediction error. We also find no association between brain age error and cognitive performance in this typically-developing sample.Overall, this study shows that, while brain age estimates based on cortical development are relatively robust and consistent across model types and preprocessing strategies, significant between-subject variation exists in the features that explain erroneous brain age predictions on an individual level.

Disentangling Cognitive Heterogeneity in Psychotic Spectrum Disorders

Neuropsychological impairments represent a central feature of psychosis-spectrum disorders. It is characterized by a great both within- and between-subjects variability (i.e. cognitive heterogeneity), which needs to be better disentangled. The present study aimed to describe the distribution of performance on the Brief Assessment of Cognition in Schizophrenia (BACS) by using the Equivalent Scores, in order to balance statistical methodological problems. To do so, cognitive performance groups were branded, identifying the main factors contributing to cognitive heterogeneity. A sample of 583 patients with a diagnosis of Schizophrenia or Psychotic Disorder Not Otherwise Specified was enrolled and assessed for neurocognition and intellectual level. K-means cluster analysis was performed based on BACS Equivalent Scores. Differences among clusters were analyzed throughout Analysis of Variance and Discriminant Function Analysis in order to identify the most significant predictors of cluster membership. For each cognitive task, roughly 40% of patients displayed poor performance, while up to 63% displayed a symbol-coding deficit. K-means cluster analysis depicted three profiles characterized by "near-normal" cognition, widespread impairment, and "borderline" profile. Discriminant analysis selected Verbal IQ and diagnosis as predictors of cluster membership. Our findings support the usefulness of Equivalent Scores and cluster analysis to explain cognitive heterogeneity, and tailor better interventions.

Population pharmacokinetic model of subcutaneous fentanyl in older acute care patients.

Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 μg) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h-1 (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h-1 (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and Cmax. This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect.

Responses to gait retraining using pressure-based auditory feedback for medial knee osteoarthritis

Responses to gait retraining using pressure-based auditory feedback for medial knee osteoarthritis

Biological variation of serum neurofilament light chain.

The neurofilament light chain (NfL) has emerged as a versatile biomarker for CNS-diseases and is approaching clinical use. The observed changes in NfL levels are frequently of limited magnitude and in order to make clinical decisions based on NfL measurements, it is essential that biological variation is not confused with clinically relevant changes. The present study was designed to evaluate the biological variation of serum NfL. Apparently healthy individuals (n=33) were submitted to blood draws for three days in a row. On the second day, blood draws were performed every third hour for 12h. NfL was quantified in serum using the Simoa™ HD-1 platform. The within-subject variation (CVI) and between-subject variation (CVG) were calculated using linear mixed-effects models. The overall median value of NfL was 6.3pg/mL (range 2.1-19.1). The CVI was 3.1% and the CVG was 35.6%. An increase in two serial measurements had to exceed 24.3% to be classified as significant at the 95% confidence level. Serum NfL levels remained stable during the day (p=0.40), whereas a minute variation (6.0-6.6pg/mL) was observed from day-to-day (p=0.02). Serum NfL is subject to tight homeostatic regulation with none or neglectable semidiurnal and day-to-day variation, but considerable between-subject variation exists. This emphasizes serum NfL as a well-suited biomarker for disease monitoring, but warrants caution when interpreting NfL levels in relation to reference intervals in a diagnosis setting. Furthermore, NfL's tight regulation requires that the analytical variation is kept at a minimum.

Population Pharmacokinetic Modelling of Orally Administered Doxycycline to Rabbits at Different Ages.

Doxycycline is a well-tolerated tetracycline antibiotic, registered for use in rabbits and administered for treatment of bacterial infections in this animal species. Nevertheless, the available pharmacokinetic data are limited and this study aimed to investigate the pharmacokinetics of orally administered doxycycline in mature and immature rabbits by application of the population approach. The rabbits were treated orally with doxycycline hyclate (5 mg/kg bw) in the form of a solid gelatin capsules. Free plasma concentrations were determined with HPLC analysis with Photodiode array detection. The estimated typical value of volume of distribution (tvV), total body clearance, and absorption rate constant were 4.429 L/kg, 1.473 L/kg/h, and 0.257 h−1, respectively. The highest between-subject variability (BSV) of 69.30% was observed for tvV. Co-variates such as body weight, age, and biochemical parameters did not improve the tested model and did not contribute to explanation of the BSV. The population pharmacokinetic model of the orally administered doxycycline in rabbits should be further developed by addition of data from more animals treated with higher doses. An oral dose of 5 mg/kg could ensure percentage of the time from the dosing interval during which the concentration is above minimum inhibitory concentration (MIC) %fT > MIC of 35% if MIC of 0.18 μg·mL−1 and a dosing interval of 12 h is assumed which does not cover criteria for rational use of antibiotics.

A semi-mechanistic exposure\u2013response model to assess the effects of verinurad, a potent URAT1 inhibitor, on serum and urine uric acid in patients with hyperuricemia-associated diseases

Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure–response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose–response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.

Biological variation and analytical goals of four thyroid function biomarkers in healthy European volunteers.

Interpretation of thyroid function tests by means of biological variation (BV) data is essential to identify significant changes between serial measurements at an individual level. Data on thyroid parameters in adults are limited. We aimed at determining the BV of four thyroid function test (thyroid-stimulating hormone (TSH), free thyroxin (FT4), free triiodothyronine (FT3) and thyroglobulin (Tg)) by applying recent recommendations to acquire BV data on a latest generation of immunoassay. Nineteen healthy volunteers (8 males and 11 females) were drawn every week during 5 consecutive weeks. Samples were analysed in duplicate on the Cobas 602 analyzer (Roche Diagnostics). After normality assessment, outlier exclusion and homogeneity of variance analysis, analytical variation (CVA ), within-subject biological variation (CVI ) and between-subject biological variation (CVG ) were determined using nested ANOVA. CVA , CVI and CVG were 0.9%, 19.7% and 37.6% for TSH; 3.6%, 4.6% and 10.8% for FT4; 2.2%, 6.0% and 8.6% for FT3; and 0.9%, 15.4% and 84.9% for Tg. Index of individuality (II) for all parameters was between 0.2 and 0.7. The percentage above which the change between two measures is truly significant (reference change value) was 54.7% for TSH, 16.2% for FT4, 17.7% for FT3 and 42.8% for Tg. Based on recent international recommendations, our study provides updated BV data for four thyroid function tests in European healthy volunteers. Reliable BV characteristics, and especially RCV, can facilitate the interpretation of consecutive thyroid function tests in an individual and therefore have the potential to efficiently support clinical decisions regarding thyroid diseases.

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug-resistant tuberculosis.

Ethionamide is part of the drug-resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment. This was an observational population PK study of patients admitted for drug-resistant tuberculosis at a hospital in South Africa. Nonlinear mixed-effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5-5μg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0-24h was 140.5μg*h/mL, which corresponds to the PK/PD target ratio AUC0-24h /MIC of 56.2. A one-compartment pharmacokinetic model with a lag-time, first-order absorption and elimination best described the PK of ethionamide. The lag-time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h-1 , 180 L and 99.5L/h, respectively, for a typical individual weighing 52.6kg. Between-subject variability in lag-time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15-20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33-50, 51-70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0-24h , respectively. There is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.

Short-Term Test-Retest Reliability of Contralateral Suppression of Click-Evoked Otoacoustic Emissions in Normal-Hearing Subjects.

Purpose The objective of the current study was to investigate the short-term test-retest reliability of contralateral suppression (CS) of click-evoked otoacoustic emissions (CEOAEs) using commercially available otoacoustic emission equipment. Method Twenty-three young normal-hearing subjects were tested. An otoscopic evaluation, admittance measures, pure-tone audiometry, measurements of CEOAEs without and with contralateral acoustic stimulation (CAS) to determine CS were performed at baseline (n = 23), an immediate retest without and with refitting of the probe (only CS of CEOAEs; n = 11), and a retest after 1 week (n = 23) were performed. Test-retest reliability parameters were determined on CEOAE response amplitudes without and with CAS, and on raw and normalized CS indices between baseline and the other test moments. Results Repeated-measures analysis of variance indicated no random or systematic changes in CEOAE response amplitudes without and with CAS, and in raw and normalized CS indices between the test moments. Moderate-to-high intraclass correlation coefficients with mostly high significant between-subjects variability between baseline and each consecutive test moment were found for CEOAE response amplitude without and with CAS, and for the raw and normalized CS indices. Other reliability parameters deteriorated between CEOAE response amplitudes with CAS as compared to without CAS, between baseline and retest with probe refitting, and after 1 week, as well as for frequency-specific raw and normalized CS indices as compared to global CS indices. Conclusions There was considerable variability in raw and normalized CS indices as measured using CEOAEs with CAS using commercially available otoacoustic emission equipment. More research is needed to optimize the measurement of CS of CEOAEs and to reduce influencing factors, as well as to make generalization of test-retest reliability data possible.

Population pharmacokinetics and pharmacodynamics of Tranexamic acid in women undergoing caesarean delivery.

The population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies. We analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15mg/kg of TXA intravenously using population approach. TXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4L/h (27.7%), central volume of 10.1L (47.4%), intercompartmental clearance of 22.4L/h (66.7%), peripheral volume of 14.0L (13.1%) and additive error of 1.4mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650mg of TXA maintained therapeutic targets for 30minutes and 1hour, respectively, in 90% of patients. This is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650mg dose provides adequate PPH prophylaxis up to 1hour, which is less than the currently used 1000mg of TXA in pregnant women.

Population Pharmacokinetic Analysis of Fevipiprant in Healthy Subjects and Asthma Patients using a Tukey’s g-and-h Distribution

Abstract Aim The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant. Methods PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach. Results Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%. Conclusion Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

The longitudinal stability of fMRI activation during reward processing in adolescents and young adults

BackgroundThe use of functional neuroimaging has been an extremely fruitful avenue for investigating the neural basis of human reward function. This approach has included identification of potential neurobiological mechanisms of psychiatric disease and examination of environmental, experiential, and biological factors that may contribute to disease risk via effects on the reward system. However, a central and largely unexamined assumption of much of this research is that neural reward function is an individual difference characteristic that is relatively stable and trait-like over time. MethodsIn two independent samples of adolescents and young adults studied longitudinally (Ns = 145 & 139, 100% female and 100% male, ages 15–21 and 20–22, 2–4 scans and 2 scans respectively), we tested within-person stability of reward-task BOLD activation, with a median of 1 and 2 years between scans. We examined multiple commonly used contrasts of active states and baseline in both the anticipation and feedback phases of a card-guessing reward task. We examined the effects of cortical parcellation resolution, contrast, network (reward regions and resting-state networks), region-size, and activation strength and variability on the stability of reward-related activation. ResultsIn both samples, contrasts of an active state relative to a baseline were more stable (ICC: intra-class correlation; e.g., Win>Baseline; mean ICC = 0.13 – 0.33) than contrasts of two active states (e.g., Win>Loss; mean ICC = 0.048 – 0.05). Additionally, activation in reward regions was less stable than in many non-task networks (e.g., dorsal attention), and activation in regions with greater between-subject variability showed higher stability in both samples. ConclusionsThese results show that some contrasts from functional neuroimaging activation during a card guessing reward task have partially trait-like properties in adolescent and young adult samples over 1–2 years. Notably, results suggest that contrasts intended to map cognitive function and show robust group-level effects (i.e. Win > Loss) may be less effective in studies of individual differences and disease risk. The robustness of group-level activation should be weighed against other factors when selecting regions of interest in individual difference fMRI studies.

Daily activity spaces and drug use among female sex workers living with HIV in the Dominican Republic.

The purpose of this study was to explore the daily activity spaces of female sex workers living with HIV in the Dominican Republic and assess the relationship between activity path and location-based risk exposure measures and daily drug use. The study employed a micro-longitudinal observational study design using an innovative 7-day travel diary to capture daily activity routes and a 7-day mobile health (mHealth) daily diary to collect daily substance use behaviors among 51 female sex workers. To estimate between-subject variability, a series of crude and adjusted modified log-Poisson repeated measures regression models with generalized estimating equations, clustering by individual with a compound symmetry working correlation structure were fit to estimate the relative risks and 95% confidence intervals. Controlling for individual level factors, findings showed that female sex workers exposed to a higher number of risk outlets (e.g., liquor stores, bars, hotels, nightclubs, brothels, etc.) within 200 and 100-meters of sex work locations were at an increased risk of daily drug use (RRadj: 1.03, 95%CI: 1.01, 1.05, RRadj: 1.05, 95%CI: 1.01, 1.09). No association was detected between activity path exposure and daily drug use. These findings illustrate the importance of moving beyond static residential neighborhood boundaries for measuring risk exposures and highlight the significant role that daily work environments have on drug harms among a highly stigmatized and vulnerable population.