Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Visual search in ADHD, ASD and ASD + ADHD: overlapping or dissociating disorders?

Recent debates in the literature discuss commonalities between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) at multiple levels of putative causal networks. This debate requires systematic comparisons between these disorders that have been studied in isolation in the past, employing potential markers of each disorder to be investigated in tandem. The present study, choose superior local processing, typical to ASD, and increased Intra-Subject Variability (ISV), typical to ADHD, for a head-to-head comparison of the two disorders, while also considering the comorbid cases. It directly examined groups of participants aged 10-13 years with ADHD, ASD with (ASD+) or without (ASD-) comorbid ADHD and a typically developing (TD) group (total N = 85). A visual search task consisting of an array of paired words was designed. The participants needed to find the specific pair of words, where the first word in the pair was the cue word. This visual search task was selected to compare these groups on overall search performance and trial-to-trial variability of search performance (i.e., ISV). Additionally, scanpath analysis was also carried out using Recurrence Quantification Analysis (RQA) and the Multi-Match Model. Results show that only the ASD- group exhibited superior search performance; whereas, only the groups with ADHD symptoms showed increased ISV. These findings point towards a double dissociation between ASD and ADHD, and argue against an overlap between ASD and ADHD.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

PURPOSE: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. METHODS: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. RESULTS: The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject's skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. CONCLUSIONS: Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

A Pooled Analysis of Pharmacokinetic Variability Information for Common Probe Substrates Used in Drug-Drug Interaction Studies.

Sample size estimates for drug-drug interaction (DDI) studies are often based on variability information from the literature or from historical studies, but small sample sizes in these sources may limit the precision of the estimates obtained. This project aimed to create an intra-subject variability library of the pharmacokinetic (PK) exposure parameters, area under the curve, and maximum plasma concentration, for probes commonly used in DDI studies. Data from 66 individual DDI studies in healthy subjects relating to 18 common probe substrates were pooled to increase the effective sample size for the identified probes by 1.5- to 9-fold, with corresponding improvements in precision of the intra-subject PK variability estimates in this library. These improved variability estimates will allow better assessment of the sample sizes needed for DDI studies in future.

Intra-subject variability in muscle activity and co-contraction during jumps and landings in children and adults.

We investigated muscle activity, intra-subject variability in muscle activity and co-contraction during vertical jumps and landings in children and adults. Ten male children and 10 male adults completed 10 countermovement jumps (CMJ), 10 drop jumps (DJ) from 30 cm, 10 low and high landings from 30 and 60 cm for the children and 60 and 90 cm for the adults. The adults also performed ten DJ from 60 cm. EMG was recorded from nine lower limb muscles in the right leg and normalized to isometric MVC. Statistical parametric mapping was used to reveal differences in the muscle activity and intra-subject variability in the muscle activity. Co-contraction was quantified for two thigh muscle pairs and one plantar flexor/dorsiflexor muscle pair and group differences were assessed (two-way ANOVA). No significant differences were observed in the less eccentric demanding CMJ while significantly higher muscle activity magnitude and intra-subject variability were observed for the children during the initial part of the contact phase of DJ and landings, indicating a less consistent muscle activity pattern in the children. This may indicate that vertical jumps/landings involving a high amount of eccentric muscle contraction constrain the muscle activation in children, possibly because of immature motor control.

Exploring the methods of data analysis in multifocal visual evoked potentials.

PURPOSE: The multifocal visual evoked potential (mfVEP) provides a topographical assessment of visual function, which has already shown potential for use in patients with glaucoma and multiple sclerosis. However, the variability in mfVEP measurements has limited its broader application. The purpose of this study was to compare several methods of data analysis to decrease mfVEP variability. METHODS: Twenty-three normal subjects underwent mfVEP testing. Monocular and interocular asymmetry data were analyzed. Coefficients of variability in amplitude were examined using peak-to-peak, root mean square (RMS), signal-to-noise ratio (SNR) and logSNR techniques. Coefficients of variability in latency were examined using second peak and cross-correlation methods. RESULTS: LogSNR and peak-to-peak methods had significantly lower intra-subject variability when compared with RMS and SNR methods. LogSNR had the lowest inter-subject amplitude variability when compared with peak-to-peak, RMS and SNR. Average latency asymmetry values for the cross-correlation analysis were 1.7 ms (CI 95 % 1.2-2.3 ms) and for the second peak analysis 2.5 ms (CI 95 % 1.7-3.3 ms). A significant difference was found between cross-correlation and second peak analysis for both intra-subject variability (p < 0.001) and inter-subject variability (p < 0.001). CONCLUSIONS: For a comparison of amplitude data between groups of patients, the logSNR or SNR methods are preferred because of the smaller inter-subject variability. LogSNR or peak-to-peak methods have lower intra-subject variability, so are recommended for comparing an individual mfVEP to previous published normative data. This study establishes that the choice of mfVEP data analysis method can be used to decrease variability of the mfVEP results.

Reproducibility and optimization of in vivo human diffusion-weighted MRS of the corpus callosum at 3 T and 7 T.

Diffusion-weighted MRS (DWS) of brain metabolites enables the study of cell-specific alterations in tissue microstructure by probing the diffusion of intracellular metabolites. In particular, the diffusion properties of neuronal N-acetylaspartate (NAA), typically co-measured with N-acetylaspartyl glutamate (NAAG) (NAA + NAAG = tNAA), have been shown to be sensitive to intraneuronal/axonal damage in pathologies such as stroke and multiple sclerosis. Lacking, so far, are empirical assessments of the reproducibility of DWS measures across time and subjects, as well as a systematic investigation of the optimal acquisition parameters for DWS experiments, both of which are sorely needed for clinical applications of the method. In this study, we acquired comprehensive single-volume DWS datasets of the human corpus callosum at 3 T and 7 T. We investigated the inter- and intra-subject variability of empirical and modeled diffusion properties of tNAA [D(avg) (tNAA) and D(model) (tNAA), respectively]. Subsequently, we used a jackknife-like resampling approach to explore the variance of these properties in partial data subsets reflecting different total scan durations. The coefficients of variation (C(V)) and repeatability coefficients (C(R)) for D(avg) (tNAA) and D(model) (tNAA) were calculated for both 3 T and 7 T, with overall lower variability in the 7 T results. Although this work is limited to the estimation of the diffusion properties in the corpus callosum, we show that a careful choice of diffusion-weighting conditions at both field strengths allows the accurate measurement of tNAA diffusion properties in clinically relevant experimental time. Based on the resampling results, we suggest optimized acquisition schemes of 13-min duration at 3T and 10-min duration at 7 T, whilst retaining low variability (C(V) ≈ 8%) for the tNAA diffusion measures. Power calculations for the estimation of D(model )(tNAA) and D(avg) (tNAA) based on the suggested schemes show that less than 21 subjects per group are sufficient for the detection of a 10% effect between two groups in case-control studies.

Inward Leakage Variability between Respirator Fit Test Panels - Part I. Deterministic Approach.

Inter-panel variability has never been investigated. The objective of this study was to determine the variability between different anthropometric panels used to determine the inward leakage (IL) of N95 filtering facepiece respirators (FFRs) and elastomeric half-mask respirators (EHRs). A total of 144 subjects, who were both experienced and non-experienced N95 FFR users, were recruited. Five N95 FFRs and five N95 EHRs were randomly selected from among those models tested previously in our laboratory. The PortaCount Pro+ (without N95-Companion) was used to measure IL of the ambient particles with a detectable size range of 0.02 to 1 µm. The Occupational Safety and Health Administration standard fit test exercises were used for this study. IL test were performed for each subject using each of the 10 respirators. Each respirator/subject combination was tested in duplicate, resulting in a total 20 IL tests for each subject. Three 35-member panels were randomly selected without replacement from the 144 study subjects stratified by the National Institute for Occupational Safety and Health bivariate panel cell for conducting statistical analyses. The geometric mean (GM) IL values for all 10 studied respirators were not significantly different among the three randomly selected 35-member panels. Passing rate was not significantly different among the three panels for all respirators combined or by each model. This was true for all IL pass/fail levels of 1%, 2%, and 5%. Using 26 or more subjects to pass the IL test, all three panels had consistent passing/failing results for pass/fail levels of 1% and 5%. Some disagreement was observed for the 2% pass/fail level. Inter-panel variability exists, but it is small relative to the other sources of variation in fit testing data. The concern about inter-panel variability and other types of variability can be alleviated by properly selecting: pass/fail level (IL 1-5%); panel size (e.g., 25 or 35); and minimum number of subjects required to pass (e.g., 26 of 35 or 23 of 35).

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

Atypical and variable attention patterns reveal reduced contextual priors in children with autism spectrum disorder.

Accumulating evidence suggests that individuals with autism spectrum disorder (ASD) show impairments in using contextual priors to predict others' actions and make intention inference. Yet less is known about whether and how children with ASD acquire contextual priors during action observation and how contextual priors relate to their action prediction and intention inference. To form proper contextual priors, individuals need to observe the social scenes in a reliable manner and focus on socially relevant information. By employing a data-driven scan path method and areas of interest (AOI)-based analysis, the current study investigated how contextual priors would relate to action prediction and intention understanding in 4-to-9-year-old children with ASD (N = 56) and typically developing (TD) children (N = 50) during free viewing of dynamic social scenes with different intentions. Results showed that children with ASD exhibited higher intra-subject variability when scanning social scenes and reduced attention to socially relevant areas. Moreover, children with high-level action prediction and intention understanding showed lower intra-subject variability and increased attention to socially relevant areas. These findings suggest that altered fixation patterns might restrain children with ASD from acquiring proper contextual priors, which has cascading downstream effects on their action prediction and intention understanding.

Discrepancy between inter- and intra-subject variability in EEG-based motor imagery brain-computer interface: Evidence from multiple perspectives.

Introduction: Inter- and intra-subject variability are caused by the variability of the psychological and neurophysiological factors over time and across subjects. In the application of in Brain-Computer Interfaces (BCI), the existence of inter- and intra-subject variability reduced the generalization ability of machine learning models seriously, which further limited the use of BCI in real life. Although many transfer learning methods can compensate for the inter- and intra-subject variability to some extent, there is still a lack of clear understanding about the change of feature distribution between the cross-subject and cross-session electroencephalography (EEG) signal. Methods: To investigate this issue, an online platform for motor-imagery BCI decoding has been built in this work. The EEG signal from both the multi-subject (Exp1) and multi-session (Exp2) experiments has been analyzed from multiple perspectives. Results: Firstly we found that with the similar variability of classification results, the time-frequency response of the EEG signal within-subject in Exp2 is more consistent than cross-subject results in Exp1. Secondly, the standard deviation of the common spatial pattern (CSP) feature has a significant difference between Exp1 and Exp2. Thirdly, for model training, different strategies for the training sample selection should be applied for the cross-subject and cross-session tasks. Discussion: All these findings have deepened the understanding of inter- and intra-subject variability. They can also guide practice for the new transfer learning methods development in EEG-based BCI. In addition, these results also proved that BCI inefficiency was not caused by the subject's unable to generate the event-related desynchronization/synchronization (ERD/ERS) signal during the motor imagery.

What Is the Smallest Change in Pulse Wave Velocity Measurements That Can Be Attributed to Clinical Changes in Arterial Stiffness with Certainty: A Randomized Cross-Over Study.

Pulse wave velocity (PWV), a direct measure of arterial stiffness, is a promising biomarker of cardiovascular risk and a cardiovascular surrogate outcome. The resolution for detecting its smallest clinically significant change is dependent on the expected reproducibility, but there is currently no consensus on this. We estimated the PWV reproducibility in a range of intra-subject values that were observed over a 2 week period in a broad range of participants and under clinically relevant experimental conditions (two observers, morning/afternoon sessions, and number of visits) using SphygmoCor and Arteriograph devices. Each participant was recorded 12 times with each device over three visits, one week apart, and two morning and two afternoon recordings were taken per visit. The factors affecting reproducibility and the discrepancies between the consecutive PWV measurements for each device were also examined using multilevel mixed-effect models. We show that current PWV estimation guidance recommending 2 + 1 measurements is suboptimal because the PWV range was outside of the 1 m/s threshold for most of the participants, which is proposed as a minimal clinically important difference. The best reproducibility was yielded with median of four measurements and a 1.1 m/s threshold. Although PWV reproducibility and repeatability are frequently used interchangeably in studies, we demonstrated that despite their relative measures of variability (e.g., coefficient of variation) being comparable, their ranges revealed a clinically significant difference between them. We also found that different physiological variables were predictors of the discrepancy between the consecutive measurements made by the two devices, which is likely due to their distinct modes of operation. The evidence base for PWV reproducibility is limited, and more research is needed to deepen our understanding of the variation in arterial stiffness over time, as well as fluctuations within a population group and in an intervention setting.

Intra-Subject Variability in Mathematical Learning Difficulties.

Objective: Mathematical learning difficulties (MLD) are characterized by difficulties in the understanding and processing of numbers and quantities. While MLD is related mainly to numerical deficits, studies show that this population has several other cognitive difficulties. The current study examined whether the cognitive deficits consisting of cognitive instability in the form of intra-subject variability (ISV) will also characterize the performance of individuals with MLD. Method: Female adults with MLD and a matched control group performed numerical and non-numerical tasks and various ISV measures were compared between the two groups. Results: Overall, the results showed that participants with MLD had higher ISV measures, including SD, sigma, and tau, only when performing numerical tasks. Conclusions: It appears that the cognitive system of MLD participants is less consistent and noisier when performing these numerical tasks. However, this inconsistency is not a general deficiency but rather a numerically specific one, as this inconsistency does not seem to characterize the performance of individuals with MLD in tasks that do not involve numerical processing. These findings have unique importance for understanding the difficulties characterizing individuals with MLD and possible future interventions.

Pharmacokinetics and Bioequivalence of Misoprostol Tablets: An Open-Label, Randomized, Single-dose, Crossover Study With Healthy Chinese Volunteers.

Misoprostol is a synthetic prostaglandin E1 derivative that has been used to treat duodenal and gastric ulcers, and to prevent ulcers caused by nonsteroidal anti-inflammatory drugs in many countries. Misoprostol can also be used for medical abortion. This study aimed to investigate the pharmacokinetic profiles of misoprostol tablets (test product) by comparing them with Cytotec (200 µg) (reference product). To assess the bioequivalence between test and reference products, a two-sequence, two-period crossover study was conducted with 48 healthy Chinese subjects enrolled under fasting conditions. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was used to determine the concentration of misoprostol acid in plasma. A mixed model analysis of variance was used to calculate the bioequivalence of pharmacokinetic (PK) parameters. The point estimate of geometric mean ratios with 90% confidence intervals for the maximum observed concentration (Cmax ) and the area under the concentration-time curve (AUC0-t ) for misoprostol acid in reference and test products were 107.8% and 106.5%, respectively (range 80%-125%). Additionally, none of the secondary PK parameters presented significant differences. No severe or more than moderate adverse events were detected in the 48 subjects. However, one subject discontinued the treatment due to drug-related gastrointestinal reactions. All adverse events were mild with rates of 19.2% and 22.9% after the administration test and reference products, respectively. Overall, the bioequivalence between the two misoprostol products was demonstrated in fasting conditions, and all subjects tolerated both treatments.

The neuropsychological profile of delirium vulnerability: A systematic review and meta-analysis.

Delirium is a common neurocognitive disorder in hospitalised older adults with substantial negative consequences. Impaired global cognition is a well-established delirium risk factor. However, poor performance on attention tests and higher intra-subject variability may be more sensitive delirium risk factors, given the disorder is characterised by a fluctuating course and attentional deficits. We systematically searched databases (Embase, PsycINFO, MEDLINE) and 44 studies satisfied inclusion criteria. Random-effects meta-analysis models showed poor performance in all cognitive domains except perception was significantly associated with incident delirium. Largest effects were for orientation (g=-1.20) and construction and motor performance (g=-0.60). These effects were no longer significant in the subgroup without pre-existing cognitive impairment, where executive functions and verbal functions and language skills were associated with incident delirium. A small, non-significant association between intra-subject variability and incident delirium was found (g=0.42). Cognitive domain specific tests may be quicker and more sensitive predictors of incident delirium. This pattern of neuropsychological findings supports the proposition that vulnerability for delirium manifests as a dysfunction of whole-brain information integration.

Identifying Individuals With Mild Cognitive Impairment Using Working Memory-Induced Intra-Subject Variability of Resting-State EEGs.

Individuals with mild cognitive impairment (MCI) are at high risk of developing into dementia (e. g., Alzheimer's disease, AD). A reliable and effective approach for early detection of MCI has become a critical challenge. Although compared with other costly or risky lab tests, electroencephalogram (EEG) seems to be an ideal alternative measure for early detection of MCI, searching for valid EEG features for classification between healthy controls (HCs) and individuals with MCI remains to be largely unexplored. Here, we design a novel feature extraction framework and propose that the spectral-power-based task-induced intra-subject variability extracted by this framework can be an encouraging candidate EEG feature for the early detection of MCI. In this framework, we extracted the task-induced intra-subject spectral power variability of resting-state EEGs (as measured by a between-run similarity) before and after participants performing cognitively exhausted working memory tasks as the candidate feature. The results from 74 participants (23 individuals with AD, 24 individuals with MCI, 27 HC) showed that the between-run similarity over the frontal and central scalp regions in the HC group is higher than that in the AD or MCI group. Furthermore, using a feature selection scheme and a support vector machine (SVM) classifier, the between-run similarity showed encouraging leave-one-participant-out cross-validation (LOPO-CV) classification performance for the classification between the MCI and HC (80.39%) groups and between the AD vs. HC groups (78%), and its classification performance is superior to other widely-used features such as spectral powers, coherence, and the complexity estimated by Katz's method extracted from single-run resting-state EEGs (a common approach in previous studies). The results based on LOPO-CV, therefore, suggest that the spectral-power-based task-induced intra-subject EEG variability extracted by the proposed feature extraction framework has the potential to serve as a neurophysiological feature for the early detection of MCI in individuals.

Spontaneous Fluctuations in Oscillatory Brain State Cause Differences in Transcranial Magnetic Stimulation Effects Within and Between Individuals.

Transcranial magnetic stimulation (TMS) can cause measurable effects on neural activity and behavioral performance in healthy volunteers. In addition, TMS is increasingly used in clinical practice for treating various neuropsychiatric disorders. Unfortunately, TMS-induced effects show large intra- and inter-subject variability, hindering its reliability, and efficacy. One possible source of this variability may be the spontaneous fluctuations of neuronal oscillations. We present recent studies using multimodal TMS including TMS-EMG (electromyography), TMS-tACS (transcranial alternating current stimulation), and concurrent TMS-EEG-fMRI (electroencephalography, functional magnetic resonance imaging), to evaluate how individual oscillatory brain state affects TMS signal propagation within targeted networks. We demonstrate how the spontaneous oscillatory state at the time of TMS influences both immediate and longer-lasting TMS effects. These findings indicate that at least part of the variability in TMS efficacy may be attributable to the current practice of ignoring (spontaneous) oscillatory fluctuations during TMS. Ignoring this state-dependent spread of activity may cause great individual variability which so far is poorly understood and has proven impossible to control. We therefore also compare two technical solutions to directly account for oscillatory state during TMS, namely, to use (a) tACS to externally control these oscillatory states and then apply TMS at the optimal (controlled) brain state, or (b) oscillatory state-triggered TMS (closed-loop TMS). The described multimodal TMS approaches are paramount for establishing more robust TMS effects, and to allow enhanced control over the individual outcome of TMS interventions aimed at modulating information flow in the brain to achieve desirable changes in cognition, mood, and behavior.

EEGs Vary Less Between Lab and Home Locations Than They Do Between People.

Given the rapid development of light weight EEG devices which we have witnessed the past decade, it is reasonable to ask to which extent neuroscience could now be taken outside the lab. In this study, we have designed an EEG paradigm well suited for deployment "in the wild." The paradigm is tested in repeated recordings on 20 subjects, on eight different occasions (4 in the laboratory, 4 in the subject's own home). By calculating the inter subject, intra subject and inter location variance, we find that the inter location variation for this paradigm is considerably less than the inter subject variation. We believe the paradigm is representative of a large group of other relevant paradigms. This means that given the positive results in this study, we find that if a research paradigm would benefit from being performed in less controlled environments, we expect limited problems in doing so.

Multi-scale graph-based grading for Alzheimer's disease prediction.

The prediction of subjects with mild cognitive impairment (MCI) who will progress to Alzheimer's disease (AD) is clinically relevant, and may above all have a significant impact on accelerating the development of new treatments. In this paper, we present a new MRI-based biomarker that enables us to accurately predict conversion of MCI subjects to AD. In order to better capture the AD signature, we introduce two main contributions. First, we present a new graph-based grading framework to combine inter-subject similarity features and intra-subject variability features. This framework involves patch-based grading of anatomical structures and graph-based modeling of structure alteration relationships. Second, we propose an innovative multiscale brain analysis to capture alterations caused by AD at different anatomical levels. Based on a cascade of classifiers, this multiscale approach enables the analysis of alterations of whole brain structures and hippocampus subfields at the same time. During our experiments using the ADNI-1 dataset, the proposed multiscale graph-based grading method obtained an area under the curve (AUC) of 81% to predict conversion of MCI subjects to AD within three years. Moreover, when combined with cognitive scores, the proposed method obtained 85% of AUC. These results are competitive in comparison to state-of-the-art methods evaluated on the same dataset.

Social and non-social gaze cueing in autism spectrum disorder, attention-deficit/hyperactivity disorder and a comorbid group.

Recent trends in literature, along with the changes to the Diagnostic and Statistical Manual (DSM), make it imperative to study Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) together, in order to better understand potential aetiological commonalities between these highly comorbid disorders. The present study examines social cueing, a highly studied construct in ASD, and intra-subject variability (ISV), a potential endophenotype of ADHD, in four groups of typically developing (TD), ADHD, ASD- (ASD without ADHD), ASD+ (ASD with ADHD) participants (N = 85) aged 10-13 years. Results showed that social cueing is intact in the 'pure' ASD group when task expectations are clear. The ADHD group showed faster saccadic reaction times, no increased ISV and a pattern of viewing comparable to the TD group. However, the ASD + group showed a differences in processing style and ISV. A secondary analysis gives evidence of non-additive effects of the ASD and ADHD factors.