Identification and validation of biomarkers for autism spectrum disorders

Loth, Eva; Spooren, Will; Ham, Lindsay; Isaac, Maria; Auriche-Benichou, Caroline; Banaschewski, Tobias; Baron‐Cohen, Simon; Broich, Karl; Bölte, Sven; Bourgeron, Thomas; Charman, Tony; Collier, David A.; Andrés-Trelles, F; Durston, Sarah; Ecker, Christine; Elferink, André; Haberkamp, Marion; Hemmings, Robert; Johnson, Mark H.; Jones, Emily J. H.; Khwaja, Omar; Lenton, Sabine; Mason, Luke; Mantua, Valentina; Meyer‐Lindenberg, Andreas; Lombardo, Michael; O’Dwyer, Laurence; Okamoto, Koichi; Pandina, Gahan; Pani, Luca; Persico, Antonio M.; Simonoff, Emily; Tauscher-Wisniewski, Sitra; Llinares-Garcia, Jordi; Vamvakas, Spiros; Williams, Steve; Buitelaar, Jan K.; Murphy, Declan

doi:10.1038/nrd.2015.7

Cited by 119 publications

(103 citation statements)

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“…As described in the companion paper [46], as part of the EU-AIMS clinical research programme [47–49], we established the Longitudinal European Autism Project (LEAP). Here, we report on the baseline clinical assessment of the EU-AIMS LEAP cohort.…”

Section: Introductionmentioning

confidence: 99%

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation

et al. 2017

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BackgroundThe EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers.MethodsFrom six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms.ResultsThe cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females.ConclusionsThe established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0145-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation

et al. 2017

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“…Large-scale multi-center multidisciplinary observational studies, such as the EU-AIMS Longitudinal European Autism Project (LEAP) are currently underway that have sufficient power to identify stratification markers (44). Multi-modal assessments of each individual allow us to identify genetic, molecular, circuit-based, and behavioral markers.…”

Section: Stratification Biomarkersmentioning

confidence: 99%

“…To do this, hierarchical clustering methods (47) or normative modeling approaches to neuroimaging data (48), have recently been used. Larger-scale neuroimaging studies of ASD [e.g., EU-AIMS LEAP (44); Province of Ontario Neurodevelopmental Disorders Network, POND (49)] or efforts to aggregate neuroimaging data from different laboratories [Autism Brain Image Data Exchange, ABIDE (50)] now begin to provide cohorts of sufficient sizes and to enable replication. In contrast to the relative high costs of MRI scans, electrophysiological methods are relatively less expensive, and easy to use in young children and even infants, and individuals with intellectual disabilities (51).…”

Section: Stratification Biomarkersmentioning

confidence: 99%

Defining Precision Medicine Approaches to Autism Spectrum Disorders: Concepts and Challenges

Loth¹,

Murphy

Spooren

2016

Front. Psychiatry

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The tremendous clinical and etiological variability between individuals with autism spectrum disorder (ASD) has made precision medicine the most promising treatment approach. It aims to combine new pathophysiologically based treatments with objective tests (stratification biomarkers) to predict which treatment may be beneficial for a particular person. Here we discuss significant advances and current challenges for this approach: rare monogenic forms of ASD have provided a major breakthrough for the identification of treatment targets by providing a means to trace causal links from a gene to specific molecular alterations and biological pathways. To estimate whether treatment targets thus identified may be useful for larger patient groups we need a better understanding of whether different etiologies (i.e., genetic and environmental risk factors acting at different critical time points) lead to convergent or divergent molecular mechanisms, and how they map onto differences in circuit-level brain and cognitive development, and behavioral symptom profiles. Several recently failed clinical trials with syndromic forms of ASD provide valuable insights into conceptual and methodological issues linked to limitations in the translatability from animal models to humans, placebo effects, and a need for mechanistically plausible, objective outcome measures. To identify stratification biomarkers that enrich participant selection in clinical trials, large-scale multi-modal longitudinal observational studies are underway. Addressing these different factors in the next generation of research studies requires a translatable developmental perspective and multidisciplinary, collaborative efforts, with a commitment to sharing protocols and data, to increase transparency and reproducibility.

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“…Recently there has been an increased focus on identifying biomarkers for autism [18,19]. Many of the observations cited above regarding sulfur compounds in the blood or plasma in autism are highly statistically significant, and in some cases the average levels of these compounds in autism differ substantially from controls.…”

Section: Hypothesis Sulfur Compounds In Autism Biochemistrymentioning

confidence: 99%

Antioxidant sulfur compounds: potential therapies for autism?

Bittker¹

2016

J Autism

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Many of those with autism have biochemistry that is characterized by high levels of oxidative stress and low levels of sulfur antioxidants. Of the small set of compounds which have been shown to have some efficacy in double-blind trials in treating some aspects of autism, four are sulfur containing compounds with antioxidant properties. Specifically these four have been found to be efficacious with statistical significance in double-blind trials in autism: n-acetylcysteine, sulforaphane, l-carnitine, and a multivitamin containing methyl-sufonyl-methane and n-acetylcysteine. Each of these compounds has antioxidant properties, and there are other sulfur containing compounds with antioxidant properties which case studies suggest may have some efficacy in autism as well. The over-representation of sulfur containing antioxidants in the set of compounds that have been found to be therapeutic for autism as well as the indications of therapeutic potential of others, and the low levels of sulfur compounds and high oxidative stress that are often seen in autism biochemistry suggest that sulfur deficits are often fundamental to autism etiology, and sulfur containing antioxidants are worthy of additional study as a class of therapeutics for autism.

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Identification and validation of biomarkers for autism spectrum disorders

Cited by 119 publications

References 10 publications

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation

Defining Precision Medicine Approaches to Autism Spectrum Disorders: Concepts and Challenges

Antioxidant sulfur compounds: potential therapies for autism?

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