Incidence of emergency department presentations for traumatic brain injury in Indigenous and non-Indigenous residents aged 15–64 over the 9-year period 2007–2015 in North Queensland, Australia

Background: Traumatic brain injury (TBI) is a leading cause of disability worldwide. Previous studies have shown that males have a higher incidence than females, and Indigenous populations have a higher rate than non-Indigenous. To date, no study has compared the incidence rate of TBI between Indigenous and non-Indigenous Australians for any cause. Here we add to this rather sparse literature. Methods: Retrospective analysis of data from North Queensland Emergency Departments between 2007 and 2015 using Australian Bureau of Statistics population estimates for North Queensland residents aged 15-64 years as denominator data. Outcome measures include incidence rate ratios (IRR) for TBI presentations by Indigenous status, age, sex, year of presentation, remoteness, and socio-economic indicator. Results: Overall incidence of TBI presentations per 100,000 population was 97.8. Indigenous people had an incidence of 166.4 compared to an incidence in the non-Indigenous population of 86.3, providing an IRR of 1.93 (95% CI 1.77-2.10; p < 0.001). Males were 2.29 (95% CI 2.12-2.48; p < 0.001) times more likely to present than females. Incidence increased with year of presentation only in the Indigenous male population. Conclusions: The greater burden of ED presentations for TBI in the Indigenous compared with the non-Indigenous population is of concern. Importantly, the need to provide quality services and support to people living with TBI in remote and very remote areas, and the major role of the new National Disability Insurance Scheme is discussed.Adrian Esterman, Fintan Thompson, Michelle Fitts, John Gilroy, Jennifer Fleming, Paul Maruff, Alan Clough and India Bohann

Indigenous traumatic brain injury research: responding to recruitment challenges in the hospital environment

Background: Hospitals are common recruitment sites for injury and disability studies. However, the clinical and rehabilitation environment can create unique challenges for researchers to recruit participant populations. While there is growing injury and disability focused research involving Indigenous people to understand the types of services and supports required by this population to enhance their recovery experiences, there is limited knowledge of researchers' experiences implementing recruitment processes in the tertiary hospital environment. This paper reflects on the specific challenges of recruiting Indigenous patients following a traumatic brain injury from two tertiary hospitals in Northern Australia. Methods: Between July 2016 and April 2018, research staff recruited eligible patients from one hospital in Queensland and one hospital in the Northern Territory. Qualitative records summarising research staff contact with patients, family members and clinical hospital staff were documented. These qualitative records, in addition to field trip notes and researcher reflections were reviewed to summarise the main challenges in gaining access to patients who fit the eligibility criteria. Results: During the recruitment process, there were five main challenges encountered: (1) Patients discharging against medical advice from hospital; (2) Discharge prior to formal emergence from Post Traumatic Amnesia as per the Westmead Post Trauma Amnesia Scale; (3) Patients under adult guardianship orders; (4) Narrow participant eligibility criteria and (5) Coordinating around patient commitments and treatment. Details of how the recruitment processes were modified throughout the recruitment phase of the study to ensure greater access to patients that met the criteria are described. Conclusion: Based on our recruitment experiences, several recommendations are proposed for future TBI studies with Indigenous Australians. In addition to treatment, Indigenous TBI patients have wide range of needs that must be addressed while in hospital. Patient engagement and data collection processes should be flexible to respond to patient needs and the hospital environment. Employment of a centralized recruiter at each hospital site may help to minimise the challenges researchers need to navigate in the hospital environment. To improve recruitment processes in hospitals, it is essential for researchers examining other health or injury outcomes to describe their recruitment experiences.Michelle S. Fitts, Taeha Condon, John Gilroy, Katrina Bird, Erica Bleakley, Lauren Matheson, Jennifer Fleming, Alan R. Clough, Adrian Esterman, Paul Maruff, and India Bohann

Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington’s disease provides in vivo evidence for impaired energy metabolism

Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects the brain. Atrophy of deep grey matter structures has been reported and it is likely that underlying pathologic processes occur before, or in concurrence with, volumetric changes. Measurement of metabolite concentrations in these brain structures has the potential to provide insight into pathological processes. We aim to gain understanding of metabolite changes with respect to the disease stage and pathophysiological changes. We studied five brain regions using magnetic resonance spectroscopy (MRS) using a 7-Tesla MRI scanner. Localized proton spectra were acquired to obtain six metabolite concentrations. MRS was performed in the caudate nucleus, putamen, thalamus, hypothalamus, and frontal lobe in 44 control subjects, premanifest gene carriers and manifest HD. In the caudate nucleus, HD patients display lower NAA (p = 0.009) and lower creatine concentration (p = 0.001) as compared to controls. In the putamen, manifest HD patients show lower NAA (p = 0.024), lower creatine concentration (p = 0.027), and lower glutamate (p = 0.013). Although absolute values of NAA, creatine, and glutamate were lower, no significant differences to controls were found in the premanifest gene carriers. The lower concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD suggest deficits in neuronal integrity and energy metabolism. The changes in glutamate could support the excitotoxicity theory. These findings not only give insight into neuropathological changes in HD but also indicate that MRS can possibly be applied in future clinical trails to evaluate medication targeted at specific metabolic processes

Magnetic Resonance Imaging in Huntington's Disease.

Magnetic resonance imaging (MRI) is a noninvasive technique used routinely to image the body in both clinical and research settings. Through the manipulation of radio waves and static field gradients, MRI uses the principle of nuclear magnetic resonance to produce images with high spatial resolution, appropriate for the investigation of brain structure and function

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities