PubMed · 12153651
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Philip F Hall. 2002. Sinister misconceptions.. https://doi.org/10.1046/j.1523-536x.2002.00188.x
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Background: DNA methylation profiling is a tool that provides key support for central nervous system (CNS) tumor classification. However, diagnostically ambiguous pediatric cases may result in discordant outputs across classifiers. We developed MAGIBU, a cross-platform, projection-based framework that embeds individual methylomes into a fixed CNS reference landscape, ranking diagnostic entities by local epigenetic proximity to support clinician-led integrative diagnosis. Methods: As a proof-of-concept, we evaluated MAGIBU in eight morphologically challenging pediatric/juvenile CNS tumors with unresolved diagnoses after institutional and central pathology review. To establish a benchmark in the absence of a definitive histopathological ground truth, a consensus epigenetic reference was defined a priori for cases showing concordant results between the Heidelberg CNS Tumor Methylation Classifier and Methylscape Analysis. Comparisons were also performed with Epigenomic Digital Pathology (EpiDiP). To validate MAGIBU beyond this discovery cohort, performance was assessed at the family level across the CNS methylation spectrum (n = 678, 28 methylation families), on non-array platforms (whole-genome bisulfite sequencing and Oxford Nanopore), and in a focused analysis of the low-grade glioma and diffuse midline glioma compartment across four independent cohorts (n = 670). Results: In the discovery cohort, MAGIBU achieved high concordance with the consensus reference (Cohen's κ = 0.855), outperforming EpiDiP (κ = 0.278), which frequently placed low-grade tumors in proximity to higher-grade reference regions. Conclusions: MAGIBU provides a stable, quantitative differential diagnosis framework that mitigates the limitations of rigid categorical assignments. By leveraging a distance-based proximity metric, it offers a transparent decision-support tool that integrates effectively with clinical, radiological, and molecular data. While performance is inherently dependent on reference atlas composition, MAGIBU represents a robust complementary approach for the diagnostic workup of ambiguous CNS tumors.
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
BACKGROUND: Recent reports have highlighted the lifetime risk of malignancy from using ionizing radiation in pediatric imaging. Computed tomography (CT), which uses ionizing radiation, is employed extensively for neonatal brain imaging of term infants. Magnetic resonance (MR) provides an alternative that does not use ionizing radiation. OBJECTIVE: The purpose of this study was to assess the cross-modality agreement and interobserver agreement of CT and MR brain imaging of the term or near-term neonate. MATERIALS AND METHODS: Brain CT and MR images of 48 neonates were retrospectively reviewed by two pediatric neuroradiologists. CT and MR examinations had been obtained within 72 h of one another in all patients. CT was obtained with 5 mm collimation (KV=120, mAs=340). MR consisted of T1-weighted imaging (TR/TE=300/14; 4-mm slice thickness/1-mm gap), T2-weighted imaging (TR/TE/etl= 3000/126/16; 4-mm slice thickness/1-mm gap), and line scan diffusion imaging (LSDI) (TR/TE/b factor=1258/63/750; nominal 4-mm slice thickness/3-mm gap). The brain was categorized as normal or abnormal on both CT and MR. RESULTS: Ischemic injury was the most common brain abnormality demonstrated. McNemar's test indicated no significant difference between CT and MR test results for reader 1 (P=0.22) or reader 2 (P=0.45). The readers agreed on the presence or absence of abnormality on CT in 40 patients (83.3%) and on MR in 45 patients (93.8%). For CT, the kappa coefficient indicated excellent interobserver agreement (kappa=0.68), although the lower limit of the 95% confidence interval extends to kappa=0.55, which indicates only good-to-moderate agreement. For MR, the kappa coefficient indicated almost perfect interobserver agreement (kappa=0.88) with the 95% confidence interval extending to a lower limit of kappa=0.76, which represents excellent agreement. CONCLUSION. Because MR demonstrates findings similar to CT and has greater interobserver agreement, it appears that MR is a superior test to CT in determining brain abnormalities in the term neonate. Furthermore, since MR eliminates the use of ionizing radiation, a putative cause of malignancy, it should be the standard in neonatal brain imaging. Future efforts should be directed to improving neonatal access to MR to avoid the routine use of CT in infants.