Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are often comorbid. The purpose of this study is to explore the relationships between ASD and ADHD symptoms by applying causal modeling. We used a large phenotypic data set of 417 children with ASD and/or ADHD, 562 affected and unaffected siblings, and 414 controls, to infer a structural equation model using a causal discovery algorithm. Three distinct pathways between ASD and ADHD were identified: (1) from impulsivity to difficulties with understanding social information, (2) from hyperactivity to stereotypic, repetitive behavior, (3) a pairwise pathway between inattention, difficulties with understanding social information, and verbal IQ. These findings may inform future studies on understanding the pathophysiological mechanisms behind the overlap between ASD and ADHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s10803-017-3083-7) contains supplementary material, which is available to authorized users.

BackgroundNumerous factor analytic studies consistently support a distinction between two symptom domains of attention-deficit/hyperactivity disorder (ADHD), inattention and hyperactivity/impulsivity. Both dimensions show high internal consistency and moderate to strong correlations with each other. However, it is not clear what drives this strong correlation. The aim of this paper is to address this issue.MethodWe applied a sophisticated approach for causal discovery on three independent data sets of scores of the two ADHD dimensions in NeuroIMAGE (total N = 675), ADHD-200 (N = 245), and IMpACT (N = 164), assessed by different raters and instruments, and further used information on gender or a genetic risk haplotype.ResultsIn all data sets we found strong statistical evidence for the same pattern: the clear dependence between hyperactivity/impulsivity symptom level and an established genetic factor (either gender or risk haplotype) vanishes when one conditions upon inattention symptom level. Under reasonable assumptions, e.g., that phenotypes do not cause genotypes, a causal model that is consistent with this pattern contains a causal path from inattention to hyperactivity/impulsivity.ConclusionsThe robust dependency cancellation observed in three different data sets suggests that inattention is a driving factor for hyperactivity/impulsivity. This causal hypothesis can be further validated in intervention studies. Our model suggests that interventions that affect inattention will also have an effect on the level of hyperactivity/impulsivity. On the other hand, interventions that affect hyperactivity/impulsivity would not change the level of inattention. This causal model may explain earlier findings on heritable factors causing ADHD reported in the study of twins with learning difficulties.

Abstract. Bayesian Constraint-based Causal Discovery (BCCD) is a state-of-the-art method for robust causal discovery in the presence of latent variables. It combines probabilistic estimation of Bayesian networks over subsets of variables with a causal logic to infer causal statements. Currently BCCD is limited to discrete or Gaussian variables. Most of the real-world data, however, contain a mixture of discrete and continuous variables. We here extend BCCD to be able to handle combinations of discrete and continuous variables, under the assumption that the relations between the variables are monotonic. To this end, we propose a novel method for the efficient computation of BIC scores for hybrid Bayesian networks. We demonstrate the accuracy and efficiency of our approach for causal discovery on simulated data as well as on real-world data from the ADHD-200 competition.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder affecting both children and adults. One of the candidate genes for ADHD is DAT1, encoding the dopamine transporter. In an attempt to clarify its mode of action, we assessed brain activity during the reward anticipation phase of the Monetary Incentive Delay (MID) task in a functional MRI paradigm in 87 adult participants with ADHD and 77 controls (average age 36.5 years). The MID task activates the ventral striatum, where DAT1 is most highly expressed. A previous analysis based on standard statistical techniques did not show any significant dependencies between a variant in the DAT1 gene and brain activation [Hoogman et al. (2013); Neuropsychopharm 23:469-478]. Here, we used an alternative method for analyzing the data, that is, causal modeling. The Bayesian Constraint-based Causal Discovery (BCCD) algorithm [Claassen and Heskes (2012); Proceedings of the 28th Conference on Uncertainty in Artificial Intelligence] is able to find direct and indirect dependencies between variables, determines the strength of the dependencies, and provides a graphical visualization to interpret the results. Through BCCD one gets an opportunity to consider several variables together and to infer causal relations between them. Application of the BCCD algorithm confirmed that there is no evidence of a direct link between DAT1 genetic variability and brain activation, but suggested an indirect link mediated through inattention symptoms and diagnostic status of ADHD. Our finding of an indirect link of DAT1 with striatal activity during reward anticipation might explain existing discrepancies in the current literature. Further experiments should confirm this hypothesis. Ó 2015 Wiley Periodicals, Inc.Key words: ADHD; reward anticipation; Causal discovery; dopamine transporter Barbara Franke, Martine Hoogman, Elena Sokolova, Tom Claassen, Tom Heskes, Alejandro Arias Vasquez, and Perry Groot report no biomedical financial interests or potential conflicts of interest. Jan K. Buitelaar has been for the past 3 years a consultant to/member of advisory board of/ and/or speaker for Janssen Cilag BV, Eli Lilly, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. 508Neuropsychiatric Genetics INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is an impairing and highly heritable disorder affecting both children and adults. It is characterized by two types of symptoms, hyperactivity/impulsivity and inattention, which can occur separately or combined. ADHD is one of the most common psychiatric disorders in childhood, affecting 5-6% of children [Polanczyk et al., 2007]. Symptoms persist into adulthood in up to 60% of the childhood cases , and the average prevalence of ADHD in the adult population is between 2.5-4.9% [Simon et al., 2009]. Studies show that individuals with ADHD have altered cogniti...

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole ( n = 21) or saline ( n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional