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1. Differences in multidimensional phenotype of 2 joint pain models link early weight-bearing deficit to late depressive-like behavior in male mice

Author

Sara Hestehave, Roxana Florea, Alexander J.H. Fedorec, Maria Jevic, Lucile Mercy, Annia Wright, Oakley B. Morgan, Laurence A. Brown, Stuart N. Peirson, and Sandrine M. Géranton

Subjects
Anesthesiology, RD78.3-87.3
Abstract

Abstract. Introduction:. Chronic pain is a hallmark of joint diseases. Although these conditions are often accompanied by negative affective symptoms including depression and anxiety, these comorbidities are rarely studied simultaneously in preclinical models where they are poorly characterised. Moreover, how affective symptoms relate to the more obvious sensory and functional symptoms of joint diseases is not well understood. Here, we have addressed these gaps in knowledge. Methods:. We used 2 preclinical models of joint pain in male mice and an array of behavioural and molecular assays to fully characterise functional deficits, mechanical hypersensitivity, affective symptoms, and nociceptive signaling in joint pain, as well as investigate their relationship. Results:. Ankle joint inflammation and knee osteoarthritis induced mechanical hypersensitivity that lasted at least 3 months and that was not different between the 2 models on most days. However, the models presented with markedly different weight-bearing deficits, molecular profiles, and affective outcomes. Specifically, only the model of knee osteoarthritis was accompanied by an increase in negative affective behaviors, including early changes in circadian patterns, persistent cognitive impairments, and late development of depressive-like behavior. Importantly, the early weight-bearing deficit strongly correlated with the emotional profiles and the hypersensitivity at 3 months, suggesting that early objective functional measures may be used as predictors of long-term affective symptoms and pain. Conclusion:. The predictive value of early weight-bearing deficit could prove useful in the clinical setting for adapted therapeutic approaches for the prevention of emotional comorbidities and better pain management for patients with joint pain.

Published
2024
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2. Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project

Author

Llera, A., Brammer, M., Oakley, B., Tillmann, J., Zabihi, M., Mei, T., Charman, T., Ecker, C., Acqua, F. Dell, Banaschewski, T., Moessnang, C., Baron-Cohen, S., Holt, R., Durston, S., Murphy, D., Loth, E., Buitelaar, J. K., Floris, D. L., and Beckmann, C. F.

Subjects
Computer Science - Machine Learning, Statistics - Applications, Statistics - Computation
Abstract

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, as well as in psychiatric cohorts. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to explore relationships between multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N=764) and deeply characterised (i.e. range of clinical and cognitive instruments administered) sample of N=453 autistic individuals and N=311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies, mean and median imputation, as well as a Round Robin regression approach involving four independent multivariate regression models including a linear model, Bayesian Ridge regression, as well as several non-linear models, Decision Trees, Extra Trees and K-Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and consider in addition the KL divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This allows the selection of a unique model to impute missing data for the LEAP project and deliver a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future., Comment: 22 pages, 3 figures, 3 tables

Published
2022

4. Implementation of a local principal curves algorithm for neutrino interaction reconstruction in a liquid argon volume

Author

Back, J. J., Barker, G. J., Boyd, S. B., Einbeck, J., Haigh, M., Morgan, B., Oakley, B., Ramachers, Y. A., and Roythorne, D.

Subjects
Physics - Instrumentation and Detectors, High Energy Physics - Experiment
Abstract

A local principal curve algorithm has been implemented in three dimensions for automated track and shower reconstruction of neutrino interactions in a liquid argon time projection chamber. We present details of the algorithm and characterise its performance on simulated data sets., Comment: 14 pages, 17 figures; typing correction to Eq 5, the definition of the local covariance matrix

Published
2013
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9. Processing of social and monetary rewards in autism spectrum disorders.

Author

Baumeister, S., Moessnang, C., Bast, N., Hohmann, S., Aggensteiner, P., Kaiser, A., Tillmann, J., Goyard, D., Charman, T., Ambrosino, S., Baron-Cohen, S., Beckmann, C.F., Bölte, S., Bourgeron, T., Rausch, A., Crawley, D., Dell'Acqua, F., Dumas, G., Durston, S., Ecker, C., Floris, D.L., Frouin, V., Hayward, H., Holt, R., Johnson, M.H., Jones, E.J.H., Lai, M.C., Lombardo, M.V., Mason, L., Oakley, B., Oldehinkel, M., Persico, A.M., San José Cáceres, A., Wolfers, T., Loth, E., Murphy, D.G.M., Buitelaar, J.K., Tost, H., Meyer-Lindenberg, A., Banaschewski, T., Brandeis, D., Baumeister, S., Moessnang, C., Bast, N., Hohmann, S., Aggensteiner, P., Kaiser, A., Tillmann, J., Goyard, D., Charman, T., Ambrosino, S., Baron-Cohen, S., Beckmann, C.F., Bölte, S., Bourgeron, T., Rausch, A., Crawley, D., Dell'Acqua, F., Dumas, G., Durston, S., Ecker, C., Floris, D.L., Frouin, V., Hayward, H., Holt, R., Johnson, M.H., Jones, E.J.H., Lai, M.C., Lombardo, M.V., Mason, L., Oakley, B., Oldehinkel, M., Persico, A.M., San José Cáceres, A., Wolfers, T., Loth, E., Murphy, D.G.M., Buitelaar, J.K., Tost, H., Meyer-Lindenberg, A., Banaschewski, T., and Brandeis, D.

Abstract

Item does not contain fulltext, BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.

Published
2023

10. A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders

Author

Lombardi, L., Clerc, S. Le, Wu, C.L., Bouassida, J., Boukouaci, W., Sugusabesan, S., Richard, J.R., Lajnef, M., Tison, M., Corvoisier, P. Le, Barau, C., Banaschewski, T., Holt, R., Durston, S., Persico, A.M., Oakley, B., Loth, E., Buitelaar, J.K., Murphy, D., Leboyer, M., Zagury, J.F., Tamouza, R., Lombardi, L., Clerc, S. Le, Wu, C.L., Bouassida, J., Boukouaci, W., Sugusabesan, S., Richard, J.R., Lajnef, M., Tison, M., Corvoisier, P. Le, Barau, C., Banaschewski, T., Holt, R., Durston, S., Persico, A.M., Oakley, B., Loth, E., Buitelaar, J.K., Murphy, D., Leboyer, M., Zagury, J.F., and Tamouza, R.

Abstract

Contains fulltext : 297069.pdf (Publisher’s version ) (Open Access), Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes.

Published
2023

11. Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism.

Author

Pretzsch, C.M., Floris, D.L., Schäfer, T., Bletsch, A., Gurr, C., Lombardo, M.V., Chatham, C.H., Tillmann, J., Charman, T., Arenella, M., Jones, E., Ambrosino, S., Bourgeron, T., Dumas, G., Cliquet, F., Leblond, C.S., Loth, E., Oakley, B., Buitelaar, J.K., Baron-Cohen, S., Beckmann, C.F., Persico, A.M., Banaschewski, T., Durston, S., Freitag, C.M., Murphy, D.G.M., Ecker, C., Pretzsch, C.M., Floris, D.L., Schäfer, T., Bletsch, A., Gurr, C., Lombardo, M.V., Chatham, C.H., Tillmann, J., Charman, T., Arenella, M., Jones, E., Ambrosino, S., Bourgeron, T., Dumas, G., Cliquet, F., Leblond, C.S., Loth, E., Oakley, B., Buitelaar, J.K., Baron-Cohen, S., Beckmann, C.F., Persico, A.M., Banaschewski, T., Durston, S., Freitag, C.M., Murphy, D.G.M., and Ecker, C.

Abstract

Contains fulltext : 300029.pdf (Publisher’s version ) (Open Access), Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Published
2023

12. Autism Is Associated With Interindividual Variations of Gray and White Matter Morphology.

Author

Mei, T., Forde, N., Floris, D.L., Dell'Acqua, F., Stones, R., Ilioska, I., Durston, S., Moessnang, C., Banaschewski, T., Holt, R.J., Baron-Cohen, S., Rausch, A., Loth, E., Oakley, B., Charman, T., Ecker, C., Murphy, D.G.M., Beckmann, C.F., Llera, A., Buitelaar, J.K., Mei, T., Forde, N., Floris, D.L., Dell'Acqua, F., Stones, R., Ilioska, I., Durston, S., Moessnang, C., Banaschewski, T., Holt, R.J., Baron-Cohen, S., Rausch, A., Loth, E., Oakley, B., Charman, T., Ecker, C., Murphy, D.G.M., Beckmann, C.F., Llera, A., and Buitelaar, J.K.

Abstract

Contains fulltext : 299844.pdf (Publisher’s version ) (Open Access), BACKGROUND: Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. METHODS: We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6-30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions-A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants' GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. RESULTS: One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. CONCLUSIONS: Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas., 01 november 2023

Published
2023

14. List of Contributors

Author

Alcock, J., primary, Aoki, K., additional, Arunkumar, G., additional, Austad, S.N., additional, Ayala, F.J., additional, Bailey, D.H., additional, Balloux, F., additional, Bar-Yosef, O., additional, Barrett, H.C., additional, Baum, W.M., additional, Bilbao Leis, A., additional, Borchert, T., additional, Boyle, E., additional, Cabral, L.G., additional, Canfield, A.L., additional, Cela-Conde, C.J., additional, Cervantes, B.G., additional, Deacon, T.W., additional, DeGregori, J., additional, Dubreuil, B., additional, Feldman, M.W., additional, Finch, C.E., additional, Flinn, M.V., additional, Fumagalli, M., additional, Gagneux, P., additional, Gaudieri, S., additional, Greer, L.F., additional, Hameroff, S., additional, Henneberg, M., additional, Hill, A.K., additional, John, M., additional, Kingstone, A., additional, Kronfeldner, M., additional, Laidlaw, K.E.W., additional, Lordkipanidze, D., additional, Mallal, S., additional, McDermott, R., additional, McKenzie, K., additional, Monroe, K.R., additional, Murphy, J., additional, Nasiopoulos, E., additional, Oakley, B., additional, Peters, T., additional, Pitchappan, R.M., additional, Preuss, T.M., additional, Puts, D.A., additional, Reimers, M., additional, Risko, E.F., additional, Roland, A., additional, Rose, M.R., additional, Roughgarden, J., additional, Rozhok, A.I., additional, Rühli, F., additional, Ruse, M., additional, Rutledge, G.A., additional, Stoneking, M., additional, Templeton, A.R., additional, Tibayrenc, M., additional, Varki, A., additional, Verschuuren, G.M., additional, Wakano, J.Y., additional, Wood, B., additional, and Zampieri, F., additional

Published
2017
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16. Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project

Author

Llera, A., primary, Brammer, M., additional, Oakley, B., additional, Tillmann, J., additional, Zabihi, M., additional, Amelink, J. S., additional, Mei, T., additional, Charman, T., additional, Ecker, C., additional, Dell’Acqua, F., additional, Banaschewski, T., additional, Moessnang, C., additional, Baron-Cohen, S., additional, Holt, R., additional, Durston, S., additional, Murphy, D., additional, Loth, E., additional, Buitelaar, J. K., additional, Floris, D. L., additional, and Beckmann, C. F., additional

Published
2022
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17. Stratifying the autistic phenotype using electrophysiological indices of social perception

Author

Mason, L., Moessnang, C., Chatham, C., Ham, L., Tillmann, J., Dumas, G., Ellis, C., Leblond, C.S., Cliquet, F., Bourgeron, T., Beckmann, C.F., Charman, T., Oakley, B., Banaschewski, T., Meyer-Lindenberg, A., Baron-Cohen, S., Bölte, S., Buitelaar, J.K., Durston, S., Loth, E., Oranje, B., Persico, A., Dell'Acqua, F., Ecker, C., Johnson, M.H., Murphy, D., Jones, E.J.H., Mason, L., Moessnang, C., Chatham, C., Ham, L., Tillmann, J., Dumas, G., Ellis, C., Leblond, C.S., Cliquet, F., Bourgeron, T., Beckmann, C.F., Charman, T., Oakley, B., Banaschewski, T., Meyer-Lindenberg, A., Baron-Cohen, S., Bölte, S., Buitelaar, J.K., Durston, S., Loth, E., Oranje, B., Persico, A., Dell'Acqua, F., Ecker, C., Johnson, M.H., Murphy, D., and Jones, E.J.H.

Abstract

Item does not contain fulltext, Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.

Published
2022

18. Facial expression recognition is linked to clinical and neurofunctional differences in autism

Author

Meyer-Lindenberg, Hannah, Moessnang, C., Oakley, B., Ahmad, Jumana, Mason, Luke, Jones, Emily J. H., Beckmann, C.F., Buitelaar, J.K., Brammer, M.J., Loth, E., Meyer-Lindenberg, Hannah, Moessnang, C., Oakley, B., Ahmad, Jumana, Mason, Luke, Jones, Emily J. H., Beckmann, C.F., Buitelaar, J.K., Brammer, M.J., and Loth, E.

Abstract

Contains fulltext : 284980.pdf (Publisher’s version ) (Open Access)

Published
2022

19. Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project

Author

Brain, Ontwikkelingsstoornissen Ond., Llera, A, Brammer, M, Oakley, B, Tillmann, J, Zabihi, M, Amelink, J S, Mei, T, Charman, T, Ecker, C, Dell'Acqua, F, Banaschewski, T, Moessnang, C, Baron-Cohen, S, Holt, R, Durston, S, Murphy, D, Loth, E, Buitelaar, J K, Floris, D L, Beckmann, C F, Brain, Ontwikkelingsstoornissen Ond., Llera, A, Brammer, M, Oakley, B, Tillmann, J, Zabihi, M, Amelink, J S, Mei, T, Charman, T, Ecker, C, Dell'Acqua, F, Banaschewski, T, Moessnang, C, Baron-Cohen, S, Holt, R, Durston, S, Murphy, D, Loth, E, Buitelaar, J K, Floris, D L, and Beckmann, C F

Published
2022

22. Provider perspectives on maternal care challenges for Black and Latine women in Indiana: a qualitative interview study

Author

Lucia Guerra-Reyes, Rossmary D. Márquez-Lameda, Ruhun Wasata, and Oakley Byrne

Subjects
maternal health, Black, Latine, women, Indiana, United States, Diseases of the genitourinary system. Urology, RC870-923, The family. Marriage. Woman, HQ1-2044
Abstract

Indiana consistently ranks among the states with the highest maternal and infant mortality in the United States, particularly affecting Black and Latine communities, endangering their right to safe and respectful maternal care. Providers working with these communities are crucial in identifying challenges faced by their clients, and to inform programs and policies. We interviewed 32 clinical and community-based providers from February to April 2021 to understand their perspectives on the challenges faced by their Black and Latine clients. Participants were identified through online sources and referrals. Interviews, conducted over online video, were recorded, transcribed, and analysed following a six-step thematic approach. Six areas of challenges emerged: non-medical infrastructure and policy problems, effects of systemic racism and bias, insecurity of the Latine community, dissatisfaction with maternal care delivery, issues in navigating maternal healthcare, and limitations to holistic models of care. The results demonstrate the interconnected structural, organisational, and interpersonal nature of the challenges. Though challenges were described at structural and organisational levels, the focus of state maternal care programs is largely at personal and interpersonal levels. Obstetric racism, citizenship restrictions, shortage of Black and Latine providers, and transportation issues are complex problems, requiring multilevel interventions and policies to ensure Black and Latine women can exercise their right to safe and respectful maternal care. A rights-based approach centring the needs of Black, Latine and other minoritised communities should be implemented to make effective changes with an equity focus.

Published
2024
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23. The meaning of significant mean-group differences for biomarker discovery

Author

Loth, E., Ahmad, J., Chatham, C., Lopez, B., Carter, B., Crawley, D., Oakley, B., Hayward, H., Cooke, J., San Jose Caceres, A., Bzdok, D., Jones, Emily J.H., Charman, T., Beckmann, C., Bougeron, T., Toro, R., Buitelaar, J., Murphy, D., and Duman, G.

Subjects
psyc
Abstract

Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between “cases” and “controls,” which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research—autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen’s d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the “on average” when summarising their findings in their abstracts (“autistic people have deficits in X”), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers.

Published
2021

28. COVID-19 health and social care access for autistic people: A European policy review

Author

Oakley, B., Tillman, J., Ruigrok, A., Baranger, A., Takow, C., Charman, T., Jones, Emily J.H., Cusack, J., Doherty, M., Violland, P., Agnieszka, W., Simonoff, E., Buitelaar, J., Gallagher, L., and Murphy, D.

Subjects
psyc
Abstract

Background: The global COVID-19 pandemic has had an unprecedented impact on European health and social care systems, with demands on testing, hospital and intensive care capacity exceeding available resources in many regions. This has led to concerns that some vulnerable groups,including autistic people, may be excluded from services. Methods: We reviewed policies from 15 European member states, published March-July 2020,pertaining to: 1) access to COVID-19 tests; 2) provisions for treatment, hospitalisation and intensive careunits(ICU); and 3) changes to standard health and social care. In parallel, we analysed surveydata onthelived experiences of 1,301 autistic people and caregivers. Results: Autistic peopleexperienced significant barriers accessing COVID-19services. First, despite being at elevated risk for severe illness due to co-occurring health conditions, there was a lack of accessibility ofCOVID-19 testing. Second, many COVID-19 outpatient and inpatient treatment serviceswere reported to be inaccessible -predominantly resulting from individual differences in communication needs. Third, ICU triage protocols in many European countries (directly or indirectly)resultedin discriminatory exclusion from lifesaving treatments. Last, interruptions to standard health and social care left over 70% of autistic people without everyday support. Conclusions: The COVID-19 pandemic has further exacerbated existing healthcare inequalities for autistic people, likely contributing to disproportionate increases in morbidity and mortality,mental health/behavioural difficulties and reduced qualityoflife. Current policies and guidelines regarding the accessibility of COVID-19 services require urgent update to prevent the widespread exclusion of autistic peoplefrom services, which represents a violation of international human rights law.

Published
2021

33. COVID-19 health and social care access for autistic people: European policy review

Author

Oakley, B., Tillmann, J., Ruigrok, A., Baranger, A., Takow, C., Charman, T., Jones, E., Cusack, J., Doherty, M., Violland, P., Wroczyńska, A., Simonoff, E., Buitelaar, J.K., Gallagher, L., Murphy, D.G.M., Oakley, B., Tillmann, J., Ruigrok, A., Baranger, A., Takow, C., Charman, T., Jones, E., Cusack, J., Doherty, M., Violland, P., Wroczyńska, A., Simonoff, E., Buitelaar, J.K., Gallagher, L., and Murphy, D.G.M.

Abstract

Contains fulltext : 235405.pdf (Publisher’s version ) (Open Access), BACKGROUND: The global COVID-19 pandemic has had an unprecedented impact on European health and social care systems, with demands on testing, hospital and intensive care capacity exceeding available resources in many regions. This has led to concerns that some vulnerable groups, including autistic people, may be excluded from services. METHODS: We reviewed policies from 15 European member states, published in March-July 2020, pertaining to (1) access to COVID-19 tests; (2) provisions for treatment, hospitalisation and intensive care units (ICUs); and (3) changes to standard health and social care. In parallel, we analysed survey data on the lived experiences of 1301 autistic people and caregivers. RESULTS: Autistic people experienced significant barriers when accessing COVID-19 services. First, despite being at elevated risk of severe illness due to co-occurring health conditions, there was a lack of accessibility of COVID-19 testing. Second, many COVID-19 outpatient and inpatient treatment services were reported to be inaccessible, predominantly resulting from individual differences in communication needs. Third, ICU triage protocols in many European countries (directly or indirectly) resulted in discriminatory exclusion from lifesaving treatments. Finally, interruptions to standard health and social care left over 70% of autistic people without everyday support. CONCLUSIONS: The COVID-19 pandemic has further exacerbated existing healthcare inequalities for autistic people, probably contributing to disproportionate increases in morbidity and mortality, mental health and behavioural difficulties, and reduced quality of life. An urgent need exists for policies and guidelines on accessibility of COVID-19 services to be updated to prevent the widespread exclusion of autistic people from services, which represents a violation of international human rights law.

Published
2021

34. Alexithymia in autism: cross-sectional and longitudinal associations with social-communication difficulties, anxiety and depression symptoms

Author

Oakley, B., Jones, Emily J.H., Crawley, D., and Charman, T.

Subjects
psyc
Abstract

Background: Alexithymia (difficulties identifying and describing emotion) is a transdiagnostic trait implicated in social-emotional and mental health problems in the general population. Many autistic individuals experience significant social-communication difficulties and elevated anxiety/ depression and alexithymia. Nevertheless, the role of alexithymia in explaining individual variability in the quality/ severity of social-communication difficulties and/ or anxiety and depression symptoms in autism remains poorly understood. \ud Methods: 337 adolescents and adults (autism N=179) were assessed for alexithymia on the Toronto Alexithymia Scale and for social-communication difficulties, anxiety and depression symptoms. 135 individuals (autism N=76) were followed up 12-24-months later. We used regression models to establish cross-sectional and longitudinal associations between alexithymia, social-communication difficulties, anxiety and depression symptoms. \ud Results: Autistic individuals reported significantly higher alexithymia than comparison individuals (p

Published
2020

35. Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group

Author

Crawley, D., Zhang, L., Jones, E.J.H., Ahmad, J., Oakley, B., San José Cáceres, A., Charman, T., Buitelaar, J.K., Murphy, D.G.M., Chatham, C.H., Ouden, H.E.M. den, Loth, E., Crawley, D., Zhang, L., Jones, E.J.H., Ahmad, J., Oakley, B., San José Cáceres, A., Charman, T., Buitelaar, J.K., Murphy, D.G.M., Chatham, C.H., Ouden, H.E.M. den, and Loth, E.

Abstract

Contains fulltext : 225473.pdf (publisher's version ) (Open Access), Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.

Published
2020

37. A problem with empirical studies of party policy shifts: Alternative measures of party shifts are uncorrelated

Author

Lawrence Ezrow, Oakley B. Gordon, James Adams, Tzu-Ping Liu, M. Christine Phillips, and Luca Bernardi

Subjects
021110 strategic, defence & security studies, Sociology and Political Science, media_common.quotation_subject, 05 social sciences, 0211 other engineering and technologies, 02 engineering and technology, Uncorrelated, 0506 political science, Empirical research, Political science, European integration, 050602 political science & public administration, Position (finance), Ideology, Positive economics, media_common
Abstract

Many recent cross‐national studies analyse the causes and electoral consequences of party policy shifts, using party position measures derived from election manifestos, expert surveys or voter surveys. However few studies validate their findings by analysing multiple measures of party policy shifts. In this article, data on European parties’ position shifts on both European integration and left‐right ideology is analysed, showing that this is problematic because, while alternative measures of party policy positions correlate strongly in cross‐sectional analyses, alternative measures of parties’ policy shifts are essentially uncorrelated in longitudinal analyses. Suggestions are offered on how to address this problem.

Published
2019

39. Investigating the factors underlying adaptive functioning in autism in the EU-AIMS Longitudinal European Autism Project

Author

Tillmann, J., San José Cáceres, A., Chatham, C.H., Crawley, D., Holt, R., Oakley, B., Banaschewski, T., Baron-Cohen, S., Bolte, S., Buitelaar, J.K., Durston, S., Ham, L., Loth, E., Simonoff, E., Spooren, W., Murphy, D.G.M., Charman, T., Tillmann, J., San José Cáceres, A., Chatham, C.H., Crawley, D., Holt, R., Oakley, B., Banaschewski, T., Baron-Cohen, S., Bolte, S., Buitelaar, J.K., Durston, S., Ham, L., Loth, E., Simonoff, E., Spooren, W., Murphy, D.G.M., and Charman, T.

Abstract

Contains fulltext : 204820.pdf (publisher's version ) (Closed access), Individuals with autism spectrum disorder (ASD) exhibit significant impairments in adaptive functioning that impact on their ability to meet the demands of everyday life. A recurrent finding is that there is a pronounced discrepancy between level of cognitive ability and adaptive functioning, and this is particularly prominent among higher-ability individuals. However, the key clinical and demographic associations of these discrepancies remain unclear. This study included a sample of 417 children, adolescents, and adults with ASD as part of the EU-AIMS LEAP cohort. We examined how age, sex, IQ, levels of ASD symptom and autistic trait severity and psychiatric symptomatology are associated with adaptive functioning as measured by the Vineland Adaptive Behavior Scales-Second Edition and IQ-adaptive functioning discrepancies. Older age, lower IQ and higher social-communication symptoms were associated with lower adaptive functioning. Results also demonstrate that older age, higher IQ and higher social-communication symptoms are associated with greater IQ-adaptive functioning discrepancy scores. By contrast, sensory ASD symptoms, repetitive and restricted behaviors, as well as symptoms of attention deficit/hyperactivity disorder (ADHD), anxiety and depression, were not associated with adaptive functioning or IQ-adaptive functioning discrepancy scores. These findings suggest that it is the core social communication problems that define ASD that contribute to adaptive function impairments that people with ASD experience. They show for the first time that sensory symptoms, repetitive behavior and associated psychiatric symptoms do not independently contribute to adaptive function impairments. Individuals with ASD require supportive interventions across the lifespan that take account of social-communicative ASD symptom severity. Autism Res 2019, 12: 645-657. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Perio

Published
2019

41. Complex regulation of the regulator of synaptic plasticity histone deacetylase 2 in the rodent dorsal horn after peripheral injury

Author

Eleanor J. Hobbiger, Keri K Tochiki, Sandrine M Géranton, Kaveeta Rajani, Dorothy W. U. Overington, Oakley B. Morgan, and Maria Maiarù

Subjects
Male, 0301 basic medicine, Spinal Cord Dorsal Horn, Histone Deacetylase 2, nNOS, Nitric Oxide Synthase Type I, Biology, Biochemistry, Epigenesis, Genetic, Rats, Sprague-Dawley, 03 medical and health sciences, Cellular and Molecular Neuroscience, astrocyte, 0302 clinical medicine, Peripheral Nerve Injuries, medicine, Animals, Gene silencing, pain, Posterior Horn Cell, Regulation of gene expression, Neuronal Plasticity, Histone deacetylase 2, nitrosylation, Epigenetic, Gene Regulation & Genetics, HDAC2, Posterior Horn Cells, 030104 developmental biology, medicine.anatomical_structure, Astrocytes, Synaptic plasticity, Neuropathic pain, Neuralgia, Original Article, ORIGINAL ARTICLES, Neuroscience, 030217 neurology & neurosurgery, Astrocyte
Abstract

Histone deacetylases (HDACs), HDAC2 in particular, have been shown to regulate various forms of learning and memory. Since cognitive processes share mechanisms with spinal nociceptive signalling, we decided to investigate the HDAC2 expression in the dorsal horn after peripheral injury. Using immunohistochemistry, we found that spinal HDAC2 was mainly seen in neurons and astrocytes, with neuronal expression in naïve tissue 2.6 times greater than that in astrocytes. Cysteine (S)‐nitrosylation of HDAC2 releases HDAC2 gene silencing and is controlled by nitric oxide (NO). A duration of 48 h after intraplantar injection of complete Freund's adjuvant, there was an ipsilateral increase in the most important NO‐producing enzyme in pain states, nitric oxide synthase (nNOS), accompanied by an increase in HDAC2 S‐nitrosylation. Moreover, a subset of nNOS‐positive neurons expressed cFos, a known target of HDAC2, suggesting that derepression of cFos expression following HDAC2 S‐nitrosylation might occur after noxious stimulation. We saw no change in global HDAC2 expression in both short‐ and long‐term pain states. However, HDAC2 was increased in astrocytes 7 days after neuropathic injury suggesting that HDAC2 might inhibit astrocytic gene expression in neuropathic pain states. All together, our results indicate that the epigenetic regulation of transcriptional programmes in the dorsal horn after injury is cell specific. Moreover, the prominent role of NO in persistent pain states suggests that HDAC2 S‐nitrosylation could play a crucial role in the regulation of gene expression leading to hypersensitivity. Our manuscript describes for the first time the regulation of the memory regulator histone deacetylase 2 (HDAC2) in the superficial dorsal horn of adult rats following peripheral injury. Our cell‐specific approach has revealed a complex pattern of expression of spinal HDAC2 that depends on the injury and the cell type, suggesting a sophisticated regulation of gene expression by HDAC2.

Published
2016
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42. The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes

Author

Maiarù, Maria, Morgan, Oakley B., Mao, Tianqi, Breitsamer, Michaela, Bamber, Harry, Pöhlmann, Max, Schmidt, Mathias V., Winter, Gerhard, Hausch, Felix, and Géranton, Sandrine M.

Subjects
Inflammation, Male, Mice, Knockout, Paclitaxel, Interleukin-6, fungi, food and beverages, Dorsal horn, Glucocorticoid receptor, FKPB51, Stress, Vesicular phospholipid gel, Tacrolimus Binding Proteins, Mice, Receptors, Glucocorticoid, Spinal Cord, Glucocorticoid signalling, Persistent pain, Pharmacological inhibition, Animals, Neuralgia, Female, Corticosterone, Glucocorticoids, Research Paper
Abstract

Supplemental Digital Content is Available in the Text. Pharmacological blockade of FKBP51 can reduce established persistent pain states across sexes., It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.

Published
2018

45. Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus

Author

de Vries, R.P. Riley, R. Wiebenga, A. Aguilar-Osorio, G. Amillis, S. Uchima, C.A. Anderluh, G. Asadollahi, M. Askin, M. Barry, K. Battaglia, E. Bayram, O. Benocci, T. Braus-Stromeyer, S.A. Caldana, C. Cánovas, D. Cerqueira, G.C. Chen, F. Chen, W. Choi, C. Clum, A. dos Santos, R.A.C. de Lima Damásio, A.R. Diallinas, G. Emri, T. Fekete, E. Flipphi, M. Freyberg, S. Gallo, A. Gournas, C. Habgood, R. Hainaut, M. Harispe, M.L. Henrissat, B. Hildén, K.S. Hope, R. Hossain, A. Karabika, E. Karaffa, L. Karányi, Z. Kraševec, N. Kuo, A. Kusch, H. LaButti, K. Lagendijk, E.L. Lapidus, A. Levasseur, A. Lindquist, E. Lipzen, A. Logrieco, A.F. MacCabe, A. Mäkelä, M.R. Malavazi, I. Melin, P. Meyer, V. Mielnichuk, N. Miskei, M. Molnár, A.P. Mulé, G. Ngan, C.Y. Orejas, M. Orosz, E. Ouedraogo, J.P. Overkamp, K.M. Park, H.-S. Perrone, G. Piumi, F. Punt, P.J. Ram, A.F.J. Ramón, A. Rauscher, S. Record, E. Riaño-Pachón, D.M. Robert, V. Röhrig, J. Ruller, R. Salamov, A. Salih, N.S. Samson, R.A. Sándor, E. Sanguinetti, M. Schütze, T. Sepčić, K. Shelest, E. Sherlock, G. Sophianopoulou, V. Squina, F.M. Sun, H. Susca, A. Todd, R.B. Tsang, A. Unkles, S.E. van de Wiele, N. van Rossen-Uffink, D. de Castro Oliveira, J.V. Vesth, T.C. Visser, J. Yu, J.-H. Zhou, M. Andersen, M.R. Archer, D.B. Baker, S.E. Benoit, I. Brakhage, A.A. Braus, G.H. Fischer, R. Frisvad, J.C. Goldman, G.H. Houbraken, J. Oakley, B. Pócsi, I. Scazzocchio, C. Seiboth, B. vanKuyk, P.A. Wortman, J. Dyer, P.S. Grigoriev, I.V.

Abstract

Background: The fungal genus Aspergillus is of critical importance to humankind. Species include those with industrial applications, important pathogens of humans, animals and crops, a source of potent carcinogenic contaminants of food, and an important genetic model. The genome sequences of eight aspergilli have already been explored to investigate aspects of fungal biology, raising questions about evolution and specialization within this genus. Results: We have generated genome sequences for ten novel, highly diverse Aspergillus species and compared these in detail to sister and more distant genera. Comparative studies of key aspects of fungal biology, including primary and secondary metabolism, stress response, biomass degradation, and signal transduction, revealed both conservation and diversity among the species. Observed genomic differences were validated with experimental studies. This revealed several highlights, such as the potential for sex in asexual species, organic acid production genes being a key feature of black aspergilli, alternative approaches for degrading plant biomass, and indications for the genetic basis of stress response. A genome-wide phylogenetic analysis demonstrated in detail the relationship of the newly genome sequenced species with other aspergilli. Conclusions: Many aspects of biological differences between fungal species cannot be explained by current knowledge obtained from genome sequences. The comparative genomics and experimental study, presented here, allows for the first time a genus-wide view of the biological diversity of the aspergilli and in many, but not all, cases linked genome differences to phenotype. Insights gained could be exploited for biotechnological and medical applications of fungi. © 2017 The Author(s).

Published
2017

47. ‘Theory of Mind’ is not Theory of Emotion:A cautionary note on the Reading the Mind in the Eyes Test

Author

Oakley, B, Brewer, R, Bird, G, and Catmur, C

Subjects
genetic structures, mental disorders, emotion recognition, Theory of Mind, autism spectrum disorder, social cognition, alexithymia, behavioral disciplines and activities
Abstract

The ability to represent mental states (theory of mind [ToM]) is crucial in understanding individual differences in social ability and social impairments evident in conditions such as autism spectrum disorder (ASD). The Reading the Mind in the Eyes Test (RMET) is a popular measure of ToM ability, validated in part by the poor performance of those with ASD. However, the RMET requires recognition of facial emotion, which is impaired in those with alexithymia, which frequently co-occurs with ASD. Thus, it is unclear whether the RMET indexes emotion recognition, associated with alexithymia, or ToM, associated with ASD. We therefore investigated the independent contributions of ASD and alexithymia to performance on the RMET. ASD and alexithymia-matched control participants did not differ on RMET performance, whereas ASD participants demonstrated impaired performance on an alternative test of ToM, the Movie for Assessment of Social Cognition (MASC). Furthermore, alexithymia, but not ASD diagnosis, significantly influenced RMET performance but did not affect MASC performance. These results suggest that the RMET measures emotion recognition rather than ToM ability and support the alexithymia hypothesis of emotion-related deficits in ASD.

Published
2016
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50. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain

Author

Cox, Oakley B., primary, Krojer, Tobias, additional, Collins, Patrick, additional, Monteiro, Octovia, additional, Talon, Romain, additional, Bradley, Anthony, additional, Fedorov, Oleg, additional, Amin, Jahangir, additional, Marsden, Brian D., additional, Spencer, John, additional, von Delft, Frank, additional, and Brennan, Paul E., additional

Published
2016
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