26 research outputs found

    De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy

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    Background Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy. Methods Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible. Results All mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. Conclusions Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy

    Analysis of shared heritability in common disorders of the brain

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    ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

    Relationships between outdoor time, physical activity, sedentary time, and body mass index in children : a 12-country study

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    Purpose: This study investigated the relationship between outdoor time and physical activity (PA), sedentary time (SED), and body mass index z scores among children from 12 lower-middle-income, upper-middle-income, and high-income countries. Methods: In total, 6478 children (54.4% girls) aged 9-11 years participated. Outdoor time was self-reported, PA and SED were assessed with ActiGraph GT3X+ accelerometers, and height and weight were measured. Data on parental education, neighborhood collective efficacy, and accessibility to neighborhood recreation facilities were collected from parent questionnaires. Country latitude and climate statistics were collected through national weather data sources. Gender-stratified multilevel models with parental education, climate, and neighborhood variables as covariates were used to examine the relationship between outdoor time, accelerometry measures, and body mass index z scores. Results: Each additional hour per day spent outdoors was associated with higher moderate-to vigorous-intensity PA (boys: +2.8 min/d; girls: +1.4 min/d), higher light-intensity PA (boys: +2.0 min/d; girls: +2.3 min/d), and lower SED (boys: -6.3 min/d; girls: -5.1 min/d). Effect sizes were generally weaker in lower-middle-income countries. Outdoor time was not associated with body mass index z scores. Conclusions: Outdoor time was associated with higher PA and lower SED independent of climate, parental education, and neighborhood variables, but effect sizes were small. However, more research is needed in low-and middle-income countries

    Proportion of children meeting recommendations for 24-hour movement guidelines and associations with adiposity in a 12-country study

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    Background: The Canadian 24-h movement guidelines were developed with the hope of improving health and future health outcomes in children and youth. The purpose of this study was to evaluate adherence to the 3 recommendations most strongly associated with health outcomes in new 24-h movement guidelines and their relationship with adiposity (obesity and body mass index z-score) across countries participating in the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE). Methods: Cross-sectional results were based on 6128 children aged 9-11years from the 12 countries of ISCOLE. Sleep duration and moderate-to-vigorous physical activity (MVPA) were assessed using accelerometry. Screen time was measured through self-report. Body weight and height were measured. Body mass index (BMI, kgm2) was calculated, and BMI z-scores were computed using age- and sex-specific reference data from the World Health Organization. Obesity was defined as a BMI z-score>+2 SD. Meeting the overall 24-h movement guidelines was defined as: 9 to 11h/night of sleep, ≤2h/day of screen time, and at least 60min/day of MVPA. Age, sex, highest parental education and unhealthy diet pattern score were included as covariates in statistical models. Associations between meeting vs. not meeting each single recommendation (and combinations) with obesity were assessed with odds ratios calculated using generalized linear mixed models. A linear mixed model was used to examine the differences in BMI z-scores between children meeting vs. not meeting the different combinations of recommendations. Results: The global prevalence of children meeting the overall recommendations (all three behaviors) was 7%, with children from Australia and Canada showing the highest adherence (15%). Children meeting the three recommendations had lower odds ratios for obesity compared to those meeting none of the recommendations (OR=0.28, 95% CI 0.18-0.45). Compared to not meeting the 24-h movement recommendations either independently or combined, meeting them was significantly associated with a lower BMI z-score. Whenever the MVPA recommendation was included in the analysis the odds ratios for obesity were lower. Conclusions: For ISCOLE participants meeting these 3 healthy movement recommendations the odds ratios of being obese or having high BMI z-scores were lower. However, only a small percentage of children met all recommendations. Future efforts should aim to find promising ways to increase daily physical activity, reduce screen time, and ensure an adequate night's sleep in children. Trial registration: The International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) was registered at ClinicalTrials.gov (Identifier NCT01722500) (October 29, 2012)

    Sleep characteristics and health-related quality of life in 9- to 11-year-old children from 12 countries

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    Introduction: Previous studies have linked short sleep duration, poor sleep quality, and late sleep timing with lower health-related quality of life (HRQoL) in children. However, almost all studies relied solely on self-reported sleep information, and most studies were conducted in high-income countries. To address these gaps, we studied both device-measured and self-reported sleep characteristics in relation to HRQoL in a sample of children from 12 countries that vary widely in terms of economic and human development. Methods: The study sample included 6,626 children aged 9-11 years from Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. Waist-worn actigraphy was used to measure total sleep time, bedtime, wake-up time, and sleep efficiency on both weekdays and weekends. Children also reported ratings of sleep quantity and quality. HRQoL was measured by the KIDSCREEN-10 survey. Multilevel regression models were used to determine the relationships between sleep characteristics and HRQoL. Results: Results showed considerable variation in sleep characteristics, particularly duration and timing, across study sites. Overall, we found no association between device-measured total sleep time, sleep timing or sleep efficiency, and HRQoL. In contrast, self-reported ratings of poor sleep quantity and quality were associated with HRQoL. Conclusions: Self-reported, rather than device-based, measures of sleep are related to HRQoL in children. The discrepancy related to sleep assessment methods highlights the importance of considering both device-measured and self-reported measures of sleep in understanding its health effects

    Joint association of birth weight and physical activity/sedentary behavior with obesity in children ages 9-11 years from 12 countries

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    Objective: To examine the joint association of birth weight and physical activity/sedentary time with childhood obesity in 12 countries. Methods: A cross-sectional study of 5,088 children aged 9 to 11 years was conducted. Birth weight was recalled by parents or guardians. Moderate-to-vigorous physical activity (MVPA) and sedentary behavior were objectively measured using accelerometry. Results: The association of birth weight with the odds of obesity, central obesity, and high body fat was significant among children with either low MVPA or high sedentary time but not among children with either high MVPA or low sedentary time. In comparison with children with normal birth weight and high MVPA, children with high birth weight and low MVPA showed 4.48- to 5.18-fold higher odds of obesity, central obesity, and high body fat; children with normal birth weight and low MVPA showed 3.00- to 3.30-fold higher odds of obesity, central obesity, and high body fat, and children with high birth weight and high MVPA showed 1.16- to 1.68-fold higher odds of obesity, central obesity, and high body fat. Conclusions: High MVPA is more important than high birth weight as a correlate of obesity in children

    Decolonising Public Health: Applying epidemiology and Indigenous worldview to how health and well-being is considered by Aboriginal and Torres Strait Islander people

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    This thesis presents a collection of applied epidemiological studies within an Aboriginal and Torres Strait Islander social, health and well-being context. I have applied mixed method approaches to epidemiological knowledge and methods to meet the required Masters of Philosophy in Applied Epidemiology (MAE) competencies. A social and cultural determinants of health framing was applied to the evaluation of a social health program, epidemiological study and data analysis study. Field work was undertaken with Aboriginal communities in the evaluation, epidemiological study and outbreak investigation and were underpinned by community engagement and community based participatory research models. The studies include: 1. Cross-sectional analysis of data from the Footprints in Time: Longitudinal Study of Indigenous Children (LSIC). The study explores the prevalence of community leadership aspirations and other future aspirations for children aged 9 to 12 years participating in Wave 8 of the LSIC study. Descriptive and analytical analyses were included to examine the association between leadership aspirations and key demographic factors: age, sex and remoteness. Additionally, I explored other self-reported aspirations for children with community leadership aspirations to further unpack leadership from a holistic perspective. I applied qualitative inquiry with LSIC key informants to contextualise the findings. An important feature of the study includes comparisons being made within an Aboriginal and Torres Strait Islander cohort, as opposed to comparisons between Indigenous and non-Indigenous people; 2. Outbreak investigation of mumps in an Aboriginal community in Queensland (Qld). The outbreak investigation took place in Yarrabah, March 2018 and was in partnership with Gurriny Yealamucka Health Service Aboriginal Corporation. The study included field epidemiology, advocacy and community engagement models of practice. Building relationships with the Aboriginal Health Workers (AHWs) was key to the study. The AHWs contributed to adaptation of a public health questionnaire and facilitated cultural brokerage between myself and the community to administer the follow-up questionnaire. I identified gaps between public health and primary health care practice and recommended practical strategies to help strength the relationship; and 3. Process evaluation of a Commonwealth funded program, Stronger Communities for Children (SCfC) was undertaken with a remote community in the Northern Territory, January to June 2018. A partnership between the ANU, Palngun Wurnangat Aboriginal Corporation, Kardu Lurruth Ngala Purrungime committee and community members guided the study. An epidemiological study was a component of the evaluation and included administering an adjusted survey instrument to collect data from the SCfC participants on cultural participation. Building community relationships was key and required a number of field visits to the community where I facilitated workshops with the main stakeholders to ensure community voice remained at the center of the study. Community input directed the study design, adaptation of the survey instrument, and development of the logic model and community researcher manual

    Knowledge and power : the tale of Aboriginal and Torres Strait Islander data

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    The phrase 'knowledge is power' is understood to mean that if individuals and groups in a society attain knowledge through transmission of knowledge (education), they attain wisdom. This wisdom is then used to assert power (Bacon and Montagu 1857). However, as Foucault (1990) argues, knowledge power recreates itself in a circular process. Therefore, who determines what knowledge is - and who has the right to speak to that knowledge - is important. In this commentary we critique the power and knowledge structures of the economic, political, social and cultural resources that are Aboriginal and Torres Strait Islander data. We then challenge the current holders of Aboriginal and Torres Strait Islander data and the colonial worldview from which such data are converted into knowledges. To map a new path, we offer solutions that are embedded in the concept of Indigenous Data Sovereignty (IDSov) and Indigenous Data Governance (IDGov)

    Indigenous data sovereignty in the era of big data and open data

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    Indigenous Data Sovereignty, in its proclamation of the right of Indigenous peoples to govern the collection, ownership, and application of data, recognises data as a cultural and economic asset. The impact of data is magnified by the emergence of Big Data and the associated impetus to open publicly held data (Open Data). Aboriginal and Torres Strait Islander peoples, families and communities, heavily overrepresented in social disadvantage–related data will also be overrepresented in the application of these new technologies, but in a data landscape, Indigenous peoples remain largely alienated from the use of data and its utilization within the channels of policy power. Existing data infrastructure, and the emerging Open Data infrastructure, neither recognise Indigenous agency and worldviews nor consider Indigenous data needs. This is demonstrated in the absence of any consideration of Indigenous data issues in Open Data discussions and publication. Thus, while the potential benefits of this data revolution are trumpeted, our marginalised social, cultural and political location suggests we will not share equally in these benefits. This paper discusses the unforeseen (and likely unseen) consequences of the influence of Open Data and Big Data and discusses how Indigenous Data Sovereignty can mediate risks while providing pathways to collective benefits
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