Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review

Abstract

Neurodevelopmental disorders – including attention‐deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders – manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome‐wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence – from two or more studies from independent research groups, with results going into the same direction – of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi‐level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost‐effectiveness, before they can be implemented in daily clinical practice.

Debate: Neurodiversity, autism and healthcare

“…Recently however, more profound changes are afoot. There is firstly a sense of a receding horizon on the scientific goals of this existing paradigm: no simple (or even complex) gene or brain biomarkers have been established (Cortese et al., 2023); second, the autism concept has expanded hugely in terms of measured prevalence but also into component distributed ‘autistic traits’ with no clear demarcation between autism and non‐autism, leading to a notion of autistic spectrum that has raised questions about the essential ‘prototypical’ autism concept itself.…”

BDNF, inflammatory and oxidative levels in treatment-naïve ADHD children treated with methylphenidate: An open cohort protocol

“…The copyright holder for this preprint this version posted March 5, 2023. ; https://doi.org/10.1101/2023.03.03.23286780 doi: medRxiv preprint heterogeneous samples of participants [12], lack of control for variables that may interfere with the results, such as diet, body mass index, short follow-up time, and level of physical activity, are some of these limitations. Moreover, the results are contradictory [98]. Here we propose a protocol trying to make clear clinical and biomarkers in response to medication in a cohort well characterized in a prospective follow up.…”

“…Many studies were cross-sectional and retrospective, which allows inferring only an association between inflammation and the disorder and not a causal relationship of pathogenesis [98]. Longitudinal studies are necessary to better establish the possible relationship between ADHD, inflammation, neurotrophic, and oxidative stress [16].…”

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study

“…A plethora of modalities, including genetics, electrophysiology, and neuroimaging, are employed to identify biomarkers for ASD (1) . Yet, no reliable biomarker has been established (2) because of the complicated relationships of various factors, such as genetic and environmental factors (3, 4) , biological sex (5) , cultural factors (6) , and developmental factors (7, 8) , all of which form the heterogeneity of ASD. Neuroimaging-based biomarkers, here we call neuromarkers, hold promise in their potential to achieve greater classification accuracy with fewer participants than genetic biomarkers, which only explain 2.45% of risk variance even with more than 10,000 cases (9, 10) .…”