Impairment in inhibitory control has been postulated as an underlying hallmark of attention deficit/hyperactivity disorder (ADHD), which can be utilized as a quantitative trait for genetic studies. Here, we evaluate whether inhibitory control, measured by simple automatized prepotent response (PR) inhibition variables, is a robust discriminant function for the diagnosis of ADHD in children and can be used as an endophenotype for future genetic studies. One hundred fifty-two school children (30.9% female, 67.8% with ADHD) were recruited. The ADHD checklist was used as the screening tool, whilst the DSM-IV Mini International Neuropsychiatry Interview, neurologic interview and neurologic examination, and the WISC III FSIQ test were administered as the gold standard procedure to assert ADHD diagnosis. A Go/No-Go task using a naturalistic and automatized visual signal was administered. A linear multifactor model (MANOVA) was fitted to compare groups including ADHD status, age, and gender as multiple independent factors. Linear discriminant analysis and the receiver operating characteristic curve were used to assess the predictive performance of PR inhibition variables for ADHD diagnosis. We found that four variables of prepotent response reaction time- and prepotent response inhibition established statistically significant differences between children with and without ADHD. Furthermore, these variables generated a strong discriminant function with a total classification capability of 73, 84% specificity, 68% sensitivity, and 90% positive predictive value for ADHD diagnosis, which support reaction times as a candidate endophenotype that could potentially be used in future ADHD genetic research.
Introducción: el análisis de conglomerados de clases latentes (ACCL) es un procedimiento estadístico para agrupamientos, dependiendo de la respuesta a cada ítem. Se ha usado con el trastorno de atención hiperactividad (TDAH), para derivar tipos sutiles de casos en estudios genéticos. Objetivo: analizar los CCL de 408 miembros de 120 familias con un caso índice de TDAH, en relación con los síntomas registrados en la entrevista psiquiátrica. Pacientes y métodos: a partir de un caso índice (niño escolarizado de Barranquilla con diagnóstico estándar de oro de TDAH) se construyeron familias nucleares, las cuales de evaluaron para el diagnóstico de TDAH y comorbilidades. La muestra fue de 408 miembros de 120 familias, edad 26,6 ± 15,4 años. Con el programa para computador Latent-Gold 4,0 se hizo el ACCL con la respuesta nominal para cada síntoma de TDAH, y la presencia o no de comorbilidades con TOD y TDC. Se usó el sexo y la edad como covariables categóricas. Se hizo un análisis cruzado de cada conglomerado con el diagnóstico estándar de oro. Resultados: el mejor modelo (índices de verosimilitud) fue de 6 CCL (p Bootstrap = 0,08). El conglomerado 1 (32,5 %) son adultos, predominio de sexo femenino, probabilidad < 20 % de síntomas y comorbilidades. El segundo (17,4 %) son adultos y niños de sexo masculino con 40 a 80 % de síntomas de TDAH combinado. El grupo tres (15,7 %) son niños con ~100 % síntomas de TDAH combinado, TOD y TDC. El cuarto conglomerado (14,3 %) son adultos de ambos sexos con 20 a 50 % probabilidades de hiperactividad-impulsividad, TOD (70 %) y TDC (40 %). El grupo 5 (10,6 %) en un 80 % adultos con 30 a 90 % probabilidades de inatención sin comorbilidades. El conglomerado 6 (9,5 %) con altas probabilidades de síntomas de inatención. Conclusiones: se derivaron 6 CCL. Cuatro conglomerados son de afectados, 1 de no afectados y 1 con similar proporción de afectados y no afectados, los cuales podrían ser usados en análisis con marcadores genéticos de susceptibilidad para TDAH.
Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.
Temporal processing (TP) is associated with functions such as perception, verbal skills, temporal perspective, and future planning, and is intercorrelated with working memory, attention, and inhibitory control, which are highly impaired in individuals with attention deficit hyperactivity disorder (ADHD). Here we evaluate TP measures as potential endophenotypes in Caribbean families ascertained from probands affected by ADHD. A total of 232 individuals were recruited and clinically evaluated using an extensive battery of neuropsychological tasks and reaction time (RT)-based task paradigms. Further, the heritability (genetic variance underpinning phenotype) was estimated as a measure of the genetics apportionment. A predictive framework for ADHD diagnosis was derived using these tasks. We found that individuals with ADHD differed from controls in neuropsychological tasks assessing mental control, visual-verbal memory, verbal fluency, verbal, and semantic fluency. In addition, TP measures such as RT, errors, and variability were also affected in individuals with ADHD. Moreover, we determined that only omission and commission errors had significant heritability. In conclusion, we have disentangled omission and commission errors as possible TP endophenotypes in ADHD, which can be suitable to assess the neurobiological and genetic basis of ADHD. A predictive model using these endophenotypes led to remarkable sensitivity, specificity, precision and classification rate for ADHD diagnosis, and may be a useful tool for patients’ diagnosis, follow-up, and longitudinal assessment in the clinical setting.
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