. 2023 Feb;22(1):129-149.

doi: 10.1002/wps.21037.

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

Samuele Cortese^{1

2

3

4

5}, Marco Solmi^{1

6

7

8

9}, Giorgia Michelini^{10

11}, Alessio Bellato¹², Christina Blanner¹³, Andrea Canozzi¹⁴, Luis Eudave¹⁵, Luis C Farhat¹⁶, Mikkel Højlund^{17

18}, Ole Köhler-Forsberg^{19

20}, Douglas Teixeira Leffa^{21

22}, Christopher Rohde^{20

23}, Gonzalo Salazar de Pablo^{24

25

26

27}, Giovanni Vita¹⁴, Rikke Wesselhoeft^{18

28}, Joanna Martin²⁹, Sarah Baumeister³⁰, Natali S Bozhilova^{24

31}, Christina O Carlisi³², Virginia Carter Leno³³, Dorothea L Floris^{34

35}, Nathalie E Holz^{30

35

36

37}, Eline J Kraaijenvanger³⁰, Seda Sacu³⁰, Isabella Vainieri³⁸, Giovanni Ostuzzi¹⁴, Corrado Barbui¹⁴, Christoph U Correll^{9

39

40

41}

Affiliations

¹ Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
² Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
³ Solent NHS Trust, Southampton, UK.
⁴ Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA.
⁵ Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.
⁶ Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.
⁷ Department of Mental Health, Ottawa Hospital, Ottawa, ON, Canada.
⁸ Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada.
⁹ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
¹⁰ Department of Biological & Experimental Psychology, School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
¹¹ Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
¹² School of Psychology, University of Nottingham, Semenyih, Malaysia.
¹³ Mental Health Center, Glostrup, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
¹⁴ Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
¹⁵ Faculty of Education and Psychology, University of Navarra, Pamplona, Spain.
¹⁶ Department of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark.
¹⁸ Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
¹⁹ Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
²⁰ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²¹ ADHD Outpatient Program & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
²² Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
²⁴ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁵ Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK.
²⁶ Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁷ Institute of Psychiatry and Mental Health, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, CIBERSAM, Madrid, Spain.
²⁸ Child and Adolescent Mental Health Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark.
²⁹ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
³⁰ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
³¹ School of Psychology, University of Surrey, Guilford, UK.
³² Division of Psychology and Language Sciences, University College London, London, UK.
³³ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁴ Department of Psychology, University of Zurich, Zurich, Switzerland.
³⁵ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.
³⁶ Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
³⁷ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany.
³⁸ Department of Clinical, Educational and Health Psychology, University College London, London, UK.
³⁹ Psychiatry Research, Northwell Health, Zucker Hillside Hospital, New York, NY, USA.
⁴⁰ Department of Psychiatry and Molecular Medicine, Zucker School of Medicine, Hempstead, NY, USA.
⁴¹ Center for Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.

PMID: 36640395
PMCID: PMC9840506
DOI: 10.1002/wps.21037

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

Samuele Cortese et al. World Psychiatry. 2023 Feb.

. 2023 Feb;22(1):129-149.

doi: 10.1002/wps.21037.

Authors

Affiliations

¹ Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
² Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
³ Solent NHS Trust, Southampton, UK.
⁴ Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA.
⁵ Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, UK.
⁶ Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.
⁷ Department of Mental Health, Ottawa Hospital, Ottawa, ON, Canada.
⁸ Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada.
⁹ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
¹⁰ Department of Biological & Experimental Psychology, School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK.
¹¹ Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
¹² School of Psychology, University of Nottingham, Semenyih, Malaysia.
¹³ Mental Health Center, Glostrup, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
¹⁴ Department of Neuroscience, Biomedicine, and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.
¹⁵ Faculty of Education and Psychology, University of Navarra, Pamplona, Spain.
¹⁶ Department of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark.
¹⁸ Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
¹⁹ Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
²⁰ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
²¹ ADHD Outpatient Program & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
²² Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Affective Disorders, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
²⁴ Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁵ Child and Adolescent Mental Health Services, South London and Maudsley NHS Foundation Trust, London, UK.
²⁶ Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁷ Institute of Psychiatry and Mental Health, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, CIBERSAM, Madrid, Spain.
²⁸ Child and Adolescent Mental Health Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark.
²⁹ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
³⁰ Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
³¹ School of Psychology, University of Surrey, Guilford, UK.
³² Division of Psychology and Language Sciences, University College London, London, UK.
³³ Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³⁴ Department of Psychology, University of Zurich, Zurich, Switzerland.
³⁵ Donders Institute for Brain, Cognition, and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.
³⁶ Department for Cognitive Neuroscience, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
³⁷ Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany.
³⁸ Department of Clinical, Educational and Health Psychology, University College London, London, UK.
³⁹ Psychiatry Research, Northwell Health, Zucker Hillside Hospital, New York, NY, USA.
⁴⁰ Department of Psychiatry and Molecular Medicine, Zucker School of Medicine, Hempstead, NY, USA.
⁴¹ Center for Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.

PMID: 36640395
PMCID: PMC9840506
DOI: 10.1002/wps.21037

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.

Keywords: ADHD; Biological markers; autism spectrum disorder; communication disorders; genome-wide association studies; intellectual disability; motor disorders; neurodevelopmental disorders; neuroimaging; neurophysiology; specific learning disorders; tic disorders.

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**Figure 1**
PRISMA 2020 flow diagram showing selection of studies for inclusion

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References

1. FDA‐NIH Biomarker Working Group . BEST (Biomarkers, EndpointS, and other Tools) resource. Bethesda: National Institutes of Health, 2016. - PubMed
1. García‐Gutiérrez MS, Navarrete F, Sala F et al. Biomarkers in psychiatry: concept, definition, types and relevance to the clinical reality. Front Psychiatry 2020;11:432. - PMC - PubMed
1. McGorry P, Keshavan M, Goldstone S et al. Biomarkers and clinical staging in psychiatry. World Psychiatry 2014;13:211‐23. - PMC - PubMed
1. Lutz W, Schwartz B. Trans‐theoretical clinical models and the implementation of precision mental health care. World Psychiatry 2021;20:380‐1. - PMC - PubMed
1. Maj M, van Os J, De Hert M et al. The clinical characterization of the patient with primary psychosis aimed at personalization of management. World Psychiatry 2021;20:4‐33. - PMC - PubMed

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

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

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