Commentary: Objective aids for the assessment of ADHD - further clarification of what FDA approval for marketing means and why NEBA might help clinicians. A response to Arns et al. (2016).

Neuropsychiatric EEG-Based ADHD Assessment Aid (NEBA) is an EEG-based device designed to aid in the diagnostic process for ADHD by identifying individuals less likely to have ADHD by virtue of a lower theta/beta ratio. In using NEBA as an example, the Arns et al. commentary misstates the purpose of NEBA, which is to widen the differential rather than to make the diagnosis. Arns et al. caution about missing an ADHD diagnosis, but fail to mention the impact of overdiagnosis. If we are to advance our knowledge of the etiology and pathophysiology of ADHD, as well as develop tailored treatments and ultimately improve outcomes for ADHD, then biomarkers and objective assessment aids such as NEBA are needed to improve and refine diagnostic accuracy beyond symptom description and clinical history.

Integration of an EEG biomarker with a clinician's ADHD evaluation.

BACKGROUND: This study is the first to evaluate an assessment aid for attention-deficit/hyperactivity disorder (ADHD) according to both Class-I evidence standards of American Academy of Neurology and De Novo requirements of US Food and Drug Administration. The assessment aid involves a method to integrate an electroencephalographic (EEG) biomarker, theta/beta ratio (TBR), with a clinician's ADHD evaluation. The integration method is intended as a step to help improve certainty with criterion E (i.e., whether symptoms are better explained by another condition). METHODS: To evaluate the assessment aid, investigators conducted a prospective, triple-blinded, 13-site, clinical cohort study. Comprehensive clinical evaluation data were obtained from 275 children and adolescents presenting with attentional and behavioral concerns. A qualified clinician at each site performed differential diagnosis. EEG was collected by separate teams. The reference standard was consensus diagnosis by an independent, multidisciplinary team (psychiatrist, psychologist, and neurodevelopmental pediatrician), which is well-suited to evaluate criterion E in a complex clinical population. RESULTS: Of 209 patients meeting ADHD criteria per a site clinician's judgment, 93 were separately found by the multidisciplinary team to be less likely to meet criterion E, implying possible overdiagnosis by clinicians in 34% of the total clinical sample (93/275). Of those 93, 91% were also identified by EEG, showing a relatively lower TBR (85/93). Further, the integration method was in 97% agreement with the multidisciplinary team in the resolution of a clinician's uncertain cases (35/36). TBR showed statistical power specific to supporting certainty of criterion E per the multidisciplinary team (Cohen's d, 1.53). Patients with relatively lower TBR were more likely to have other conditions that could affect criterion E certainty (10 significant results; P ≤ 0.05). Integration of this information with a clinician's ADHD evaluation could help improve diagnostic accuracy from 61% to 88%. CONCLUSIONS: The EEG-based assessment aid may help improve accuracy of ADHD diagnosis by supporting greater criterion E certainty.

Blinded, multi-center validation of EEG and rating scales in identifying ADHD within a clinical sample.

Previous validation studies of attention deficit/hyperactivity disorder (ADHD) assessment by rating scales or EEG have provided Class-IV evidence per standards of the American Academy of Neurology. To investigate clinical applications, we collected Class-I evidence, namely from a blinded, prospective, multi-center study of a representative clinical sample categorized with a clinical standard. Participating males (101) and females (58) aged 6 to 18 had presented to one of four psychiatric and pediatric clinics because of the suspected presence of attention and behavior problems. DSM-IV diagnosis was performed by clinicians assisted with a semi-structured clinical interview. EEG (theta/beta ratio) and ratings scales (Conners Rating Scales-Revised and ADHD Rating Scales-IV) were collected separately in a blinded protocol. ADHD prevalence in the clinical sample was 61%, whereas the remainder had other childhood/adolescent disorders or no diagnosis. Comorbidities were observed in 66% of ADHD patients and included mood, anxiety, disruptive, and learning disorders at rates similar to previous findings. EEG identified ADHD with 87% sensitivity and 94% specificity. Rating scales provided sensitivity of 38-79% and specificity of 13-61%. While parent or teacher identification of ADHD by rating scales was reduced in accuracy when applied to a diverse clinical sample, theta/beta ratio changes remained consistent with the clinician's ADHD diagnosis. Because theta/beta ratio changes do not identify comorbidities or alternative diagnoses, the results do not support the use of EEG as a stand-alone diagnostic and should be limited to the interpretation that EEG may complement a clinical evaluation for ADHD.

Comparison of a standard psychiatric evaluation to rating scales and EEG in the differential diagnosis of attention-deficit/hyperactivity disorder.

The objective was to investigate the effectiveness of rating scales and electroencephalography (EEG) in detecting the presence of attention-deficit/hyperactivity disorder (ADHD) within a diverse clinical sample. A standard psychiatric evaluation was used to assess 26 children/adolescents who presented to a clinic because a parent suspected the presence of ADHD. EEG data was collected in a blinded protocol, and rating scales were collected as well. Although all subjects had presented with ADHD-like symptoms, only 62% were diagnosed with ADHD, while the remaining 38% had other disorders or no diagnosis. Rating scales readily classified inattentive, impulsive, and/or hyperactive symptoms as being due to ADHD, regardless of the actual underlying disorder, leading to a sensitivity of 81% and a specificity of 22%. Previous studies have observed that there is an EEG marker that identifies ADHD vs. controls, and this marker was present in 15 out of 16 of the ADHD subjects (sensitivity=94%) and in none of the subjects with ADHD-like symptoms due to other disorders (specificity=100%). In the detection of ADHD in a diverse clinical sample, rating scales and EEG were both sensitive markers, whereas only EEG was specific. These results may have important implications to ADHD differential diagnosis.

Review of clinical validation of ADHD behavior rating scales.

The purpose of this review is to assess the range of overall accuracies for Attention Deficit/Hyperactivity Disorder (ADHD) behavior rating scales evaluated in clinical validation studies. Studies were characterized according to the evidence standards of the American Academy of Neurology (AAN). Studies were excluded due to major design problems such as overfitting by discriminant analysis. The 13 included evaluations of rating scales revealed overall accuracy in the range of 59%-79% with a pooled mean of 69% (+/-7%, standard deviation) and a pooled sample size of 2228 subjects from nine studies. While some of the excluded studies demonstrated higher overall accuracies (>79%), these studies were observed to have factors in experimen tal design and statistics that are known to unduly inflate accuracy. We recommend further research following the full AAN standards, namely well-designed, blinded, pro spective studies of rating scales applied to clinically representative samples evaluated with a clinical standard.

A meta-analysis of quantitative EEG power associated with attention-deficit hyperactivity disorder.

A meta-analysis was performed on quantitative EEG (QEEG) studies that evaluated attention-deficit hyperactivity disorder (ADHD) using the criteria of the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition). The nine eligible studies (N = 1498) observed QEEG traits of a theta power increase and a beta power decrease, summarized in the theta/beta ratio with a pooled effect size of 3.08 (95% confidence interval, 2.90, 3.26) for ADHD versus controls (normal children, adolescents, and adults). By statistical extrapolation, an effect size of 3.08 predicts a sensitivity and specificity of 94%, which is similar to previous results 86% to 90% sensitivity and 94% to 98% specificity. It is important to note that the controlled group studies were often with retrospectively set limits, and that in practice the sensitivity and specificity results would likely be more modest. The literature search also uncovered 32 pre-DSM-IV studies of ADHD and EEG power, and 29 of the 32 studies demonstrated results consistent with the meta-analysis. The meta-analytic results are also supported by the observation that the theta/beta ratio trait follows age-related changes in ADHD symptom presentation (Pearson correlation coefficient, 0.996, P = 0.004). In conclusion, this meta-analysis supports that a theta/beta ratio increase is a commonly observed trait in ADHD relative to normal controls. Because it is known that the theta/beta ratio trait may arise with other conditions, a prospective study covering differential diagnosis would be required to determine generalizability to clinical applications. Standardization of the QEEG technique is also needed, specifically with control of mental state, drowsiness, and medication.