Analysis of shared heritability in common disorders of the brain

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

GTV delineation in supraglottic laryngeal carcinoma : interobserver agreement of CT versus CT-MR delineation

Background: GTV delineation is the first crucial step in radiotherapy and requires high accuracy, especially with the growing use of highly conformal and adaptive radiotherapy techniques. If GTV delineations of observers concord, they are considered to be of high accuracy. The aim of the study is to determine the interobserver agreement for GTV delineations of supraglottic laryngeal carcinoma on CT and on CT combined with MR-images and to determine the effect of adding MR images to CT-based delineation on the delineated volume and the interobserver agreement. Methods: Twenty patients with biopsy proven T1-T4 supraglottic laryngeal cancer, treated with curative intent were included. For all patients a contrast enhanced planning CT and a 1.5-T MRI with gadolinium were acquired in the same head-and-shoulder mask for fixation as used during treatment. For MRI, a two element surface coil was used as a receiver coil. Three dedicated observers independently delineated the GTV on CT. After an interval of 2 weeks, a set of co-registered CT and MR-images was provided to delineate the GTV on CT. Common volumes (C) and encompassing volumes (E) were calculated and C/E ratios were determined for each pair of observers. The conformity index general (CIgen) was used to quantify the interobserver agreement. Results: In general, a large variation in interobserver agreement was found for CT (range: 0.29-0.77) as well as for CT-MR delineations (range: 0.17-0.80). The mean CIgen for CT (0.61) was larger compared to CT-MR (0.57) (p = 0.032). Mean GTV volume delineated on CT-MR (6.6 cm(3)) was larger compared to CT (5.6 cm(3)) (p = 0.002). Conclusion: Delineation on CT with co-registered MR-images resulted in a larger mean GTV volume and in a decrease in interobserver agreement compared to CT only delineation for supraglottic laryngeal carcinoma

GTV delineation in supraglottic laryngeal carcinoma : interobserver agreement of CT versus CT-MR delineation

Background: GTV delineation is the first crucial step in radiotherapy and requires high accuracy, especially with the growing use of highly conformal and adaptive radiotherapy techniques. If GTV delineations of observers concord, they are considered to be of high accuracy. The aim of the study is to determine the interobserver agreement for GTV delineations of supraglottic laryngeal carcinoma on CT and on CT combined with MR-images and to determine the effect of adding MR images to CT-based delineation on the delineated volume and the interobserver agreement. Methods: Twenty patients with biopsy proven T1-T4 supraglottic laryngeal cancer, treated with curative intent were included. For all patients a contrast enhanced planning CT and a 1.5-T MRI with gadolinium were acquired in the same head-and-shoulder mask for fixation as used during treatment. For MRI, a two element surface coil was used as a receiver coil. Three dedicated observers independently delineated the GTV on CT. After an interval of 2 weeks, a set of co-registered CT and MR-images was provided to delineate the GTV on CT. Common volumes (C) and encompassing volumes (E) were calculated and C/E ratios were determined for each pair of observers. The conformity index general (CIgen) was used to quantify the interobserver agreement. Results: In general, a large variation in interobserver agreement was found for CT (range: 0.29-0.77) as well as for CT-MR delineations (range: 0.17-0.80). The mean CIgen for CT (0.61) was larger compared to CT-MR (0.57) (p = 0.032). Mean GTV volume delineated on CT-MR (6.6 cm(3)) was larger compared to CT (5.6 cm(3)) (p = 0.002). Conclusion: Delineation on CT with co-registered MR-images resulted in a larger mean GTV volume and in a decrease in interobserver agreement compared to CT only delineation for supraglottic laryngeal carcinoma

Verification of HE-based CTV in laryngeal and hypopharyngeal cancer using pan-cytokeratin

Background: For accurate target definition, we determined margins for the clinical target volume (CTV) for laryngeal and hypopharyngeal cancer in computed tomography (CT, 4.3 mm), magnetic resonance imaging (MR, 6.1 mm) and fluorodeoxyglucose (FDG)-positron emission tomography (PET, 5.2 mm). Previously, we used Hematoxylin-eosin (HE) stained whole-mount sections of total laryngectomy specimens as gold standard to define CTV margins. In the present study, we verified the HE-based tumor delineation with staining for pan-cytokeratin, specific for squamous cell carcinoma. Methods: Twenty-seven patients with a T3/T4 laryngeal hypopharyngeal tumor were included. From each patient, a total laryngectomy specimen was obtained. Four subsequent 3-mm thick slices containing tumor were selected of which 4-µm thick whole-mount sections were obtained and stained with HE and for pan-cytokeratin CK-AE1/3. Tumors were microscopically delineated on both sections by an experienced head-and-neck pathologist. Tumor delineations were compared using the conformity index (CI) and the distance between both contours. Results: The CI between HE-based and CK-AE1/3-based tumor delineations was 0.87. The maximum and 95th percentile (p95) extent of the HE-based tumor delineations from the CK-AE1/3-based tumor delineations were 1.7 mm and 0.7 mm, respectively. The maximum and p95 extent of the CK-AE1/3-based tumor delineations from the HE-based tumor delineations was 1.9 mm and 0.8 mm, respectively. Conclusions: Histopathological assessment of tumor outline on standard HE-stained sections is comparable to microscopic tumor extent based on squamous cell specific pan-cytokeratin staining. Therefore, CTV margins based on HE based tumor contour will be adequate

Verification of HE-based CTV in laryngeal and hypopharyngeal cancer using pan-cytokeratin

Background: For accurate target definition, we determined margins for the clinical target volume (CTV) for laryngeal and hypopharyngeal cancer in computed tomography (CT, 4.3 mm), magnetic resonance imaging (MR, 6.1 mm) and fluorodeoxyglucose (FDG)-positron emission tomography (PET, 5.2 mm). Previously, we used Hematoxylin-eosin (HE) stained whole-mount sections of total laryngectomy specimens as gold standard to define CTV margins. In the present study, we verified the HE-based tumor delineation with staining for pan-cytokeratin, specific for squamous cell carcinoma. Methods: Twenty-seven patients with a T3/T4 laryngeal hypopharyngeal tumor were included. From each patient, a total laryngectomy specimen was obtained. Four subsequent 3-mm thick slices containing tumor were selected of which 4-µm thick whole-mount sections were obtained and stained with HE and for pan-cytokeratin CK-AE1/3. Tumors were microscopically delineated on both sections by an experienced head-and-neck pathologist. Tumor delineations were compared using the conformity index (CI) and the distance between both contours. Results: The CI between HE-based and CK-AE1/3-based tumor delineations was 0.87. The maximum and 95th percentile (p95) extent of the HE-based tumor delineations from the CK-AE1/3-based tumor delineations were 1.7 mm and 0.7 mm, respectively. The maximum and p95 extent of the CK-AE1/3-based tumor delineations from the HE-based tumor delineations was 1.9 mm and 0.8 mm, respectively. Conclusions: Histopathological assessment of tumor outline on standard HE-stained sections is comparable to microscopic tumor extent based on squamous cell specific pan-cytokeratin staining. Therefore, CTV margins based on HE based tumor contour will be adequate

Interobserver variation among pathologists for delineation of tumor on H&E-sections of laryngeal and hypopharyngeal carcinoma. How good is the gold standard?

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Outcomes of hybrid closed‐loop insulin delivery activated 24/7 versus evening and night in free‐living prepubertal children with type 1 diabetes: A multicentre, randomized clinical trial

International audienceAims: To assess the safety and efficacy of hybrid closed-loop (HCL) insulin delivery 24/7 vs. only evening and night (E/N), and on extended 24/7 use, in free-living children with T1D.Materials and methods: Pre-pubertal children (n = 122; 49F/73M, age: 8.6 ± 1.6, diabetes duration: 5.2 ± 2.3 years, insulin pump use: 4.6 ± 2.5 years, HbA1c: 7.7 ± 0.7%/61 ± 5 mmol/mol) from 4 centers were randomized for 24/7 vs. E/N activation of the Tandem Control-IQ system for 18 weeks. Afterwards, all children used the activated system 24/7 for 18 more weeks. Primary outcome was %time spent in 70-180 mg/dL glucose range (TIR).Results: HCL was active 94.1% and 51.1% of time on 24/7 and E/N modes, respectively. TIR from baseline increased more on 24/7 vs. E/N: 52.9 ± 9.5 to 67.3 ± 5.6 (+14.4%, 95CI: 12.4-16.7%) vs. 55.1 ± 10.8 to 64.7 ± 7.0 (+9.6%, 95CI: 7.4-11.6%), p = 0.001. Mean %time below range was similarly reduced from 4.2 and 4.6 to 2.7, and mean %time above range more on 24/7 mode: 41.9 to 30.0 (-11.9%, 95CI: 9.7-14.6%) vs. 39.8 to 32.6 (-7.2%, 95CI: 5.0-9.9%), p = 0.007. TIR increased through the whole range of baseline levels and always more with 24/7 use. The results were maintained during extension phase in those initially on 24/7 use and improved in those with initial E/N use up to those with 24/7 use. Neither ketoacidosis nor severe hypoglycemia occurred.Conclusions: Our study demonstrates the safety and efficacy of Tandem Control-IQ system in free-living children with T1D for both E/N and 24/7 use. 24/7 use shows better outcomes, sustained for up to 36 weeks with no safety issue. This article is protected by copyright. All rights reserved