Publications by authors named "J A S Vorstman"

108 Publications

Requirements and Operational Guidelines for Secure and Sustainable Digital Phenotyping: Design and Development Study.

J Med Internet Res 2021 Apr 7;23(4):e20996. Epub 2021 Apr 7.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands.

Background: Digital phenotyping, the measurement of human behavioral phenotypes using personal devices, is rapidly gaining popularity. Novel initiatives, ranging from software prototypes to user-ready research platforms, are innovating the field of biomedical research and health care apps. One example is the BEHAPP project, which offers a fully managed digital phenotyping platform as a service. The innovative potential of digital phenotyping strategies resides among others in their capacity to objectively capture measurable and quantitative components of human behavior, such as diurnal rhythm, movement patterns, and communication, in a real-world setting. The rapid development of this field underscores the importance of reliability and safety of the platforms on which these novel tools are operated. Large-scale studies and regulated research spaces (eg, the pharmaceutical industry) have strict requirements for the software-based solutions they use. Security and sustainability are key to ensuring continuity and trust. However, the majority of behavioral monitoring initiatives have not originated primarily in these regulated research spaces, which may be why these components have been somewhat overlooked, impeding the further development and implementation of such platforms in a secure and sustainable way.

Objective: This study aims to provide a primer on the requirements and operational guidelines for the development and operation of a secure behavioral monitoring platform.

Methods: We draw from disciplines such as privacy law, information, and computer science to identify a set of requirements and operational guidelines focused on security and sustainability. Taken together, the requirements and guidelines form the foundation of the design and implementation of the BEHAPP behavioral monitoring platform.

Results: We present the base BEHAPP data collection and analysis flow and explain how the various concepts from security and sustainability are addressed in the design.

Conclusions: Digital phenotyping initiatives are steadily maturing. This study helps the field and surrounding stakeholders to reflect upon and progress toward secure and sustainable operation of digital phenotyping-driven research.
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http://dx.doi.org/10.2196/20996DOI Listing
April 2021

A normative chart for cognitive development in a genetically selected population.

Neuropsychopharmacology 2021 Mar 29. Epub 2021 Mar 29.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.
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http://dx.doi.org/10.1038/s41386-021-00988-6DOI Listing
March 2021

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome.

Curr Psychiatry Rep 2021 02 24;23(3):13. Epub 2021 Feb 24.

Department of Psychiatry, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose Of Review: The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond.

Recent Findings: We will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective. We outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.
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http://dx.doi.org/10.1007/s11920-021-01225-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904715PMC
February 2021

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

Am J Med Genet A 2021 04 20;185(4):1120-1130. Epub 2021 Jan 20.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.
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http://dx.doi.org/10.1002/ajmg.a.62086DOI Listing
April 2021

What a finding of gene copy number variation can add to the diagnosis of developmental neuropsychiatric disorders.

Curr Opin Genet Dev 2021 Jan 14;68:18-25. Epub 2021 Jan 14.

Program in Genetics and Genome Biology, Hospital for Sick Children, Canada; The Centre for Applied Genomics, Hospital for Sick Children, Canada; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Canada. Electronic address:

Among medical disciplines, diagnosis in psychiatry depends highly upon descriptive signs and symptoms, rather than biomarkers. Clear descriptions of specific genetic etiologies have been lacking; genomic technologies, however, are rapidly changing that landscape. Notably, chromosomal microarrays-which detect gene copy number variants (CNVs)-are a recommended standard of care for neurodevelopmental disorders. As a result, an increasing number of patients now receive a clinical diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and an identified genetic etiological variant. However, psychiatric and genetic diagnoses are frequently communicated and managed as two disconnected diagnostic parameters. Here, we advocate for a transition model, allowing the integration of genetic etiological information-starting with diagnostically proven CNVs-within the DSM-5 classification framework.
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http://dx.doi.org/10.1016/j.gde.2020.12.017DOI Listing
January 2021