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Abstract Background The additive model of inheritance assumes that heterozygotes (Aa) are exactly intermediate in respect to homozygotes (AA and aa). While this model is commonly used in single-locus genetic association studies, significant deviations from additivity are well-documented and contribute to phenotypic variance across many traits and systems. This assumption can introduce type I and type II errors by overestimating or underestimating the effects of variants that deviate from additivity. Alternative genotype encoding strategies have been explored to account for different inheritance patterns, but they often incur significant computational or methodological costs. To address these challenges, we introduce PAGER (Phenotype Adjusted Genotype Encoding and Ranking), an efficient pre-processing method that encodes each genetic variant based on normalized mean phenotypic differences between diallelic genotype classes (AA, Aa, and aa). This approach more accurately reflects each variant’s true inheritance model, improving model precision while minimizing the costs associated with alternative encoding strategies. Results Through extensive benchmarking on SNPs simulated with both binary and continuous phenotypes, we demonstrate that PAGER accurately represents various inheritance patterns (including additive, dominant, recessive, and heterosis), achieves levels of statistical power that meet or exceed other encoding strategies, and attains computation speeds up to 55 times faster than a similar method, EDGE. We also apply PAGER to publicly available real-world data and identify a novel, relevant putative QTL associated with body mass index in rats (Rattus norvegicus) that is not detected with the additive model. Conclusions Overall, we show that PAGER is an efficient genotype encoding approach that can uncover sources of missing heritability and reveal novel insights in the study of complex traits while incurring minimal costs.

Abstract Purpose Epistasis, the interaction between two or more genes, is integral to the study of genetics and is present throughout nature. Yet, it is seldom fully explored as most approaches primarily focus on single-locus effects, partly because analyzing all pairwise and higher-order interactions requires significant computational resources. Furthermore, existing methods for epistasis detection only consider a Cartesian (multiplicative) model for interaction terms. This is likely limiting as epistatic interactions can evolve to produce varied relationships between genetic loci, some complex and not linearly separable. Methods We present new algorithms for the interaction coefficients for standard regression models for epistasis that permit many varied models for the interaction terms for loci and efficient memory usage. The algorithms are given for two-way and three-way epistasis and may be generalized to higher order epistasis. Statistical tests for the interaction coefficients are also provided. We also present an efficient matrix based algorithm for permutation testing for two-way epistasis. We offer a proof and experimental evidence that methods that look for epistasis only at loci that have main effects may not be justified. Given the computational efficiency of the algorithm, we applied the method to a rat data set and mouse data set, with at least 10,000 loci and 1,000 samples each, using the standard Cartesian model and the XOR model to explore body mass index. Results This study reveals that although many of the loci found to exhibit significant statistical epistasis overlap between models in rats, the pairs are mostly distinct. Further, the XOR model found greater evidence for statistical epistasis in many more pairs of loci in both data sets with almost all significant epistasis in mice identified using XOR. In the rat data set, loci involved in epistasis under the XOR model are enriched for biologically relevant pathways. Conclusion Our results in both species show that many biologically relevant epistatic relationships would have been undetected if only one interaction model was applied, providing evidence that varied interaction models should be implemented to explore epistatic interactions that occur in living systems.

Abstract Background Quantitative Trait Locus (QTL) analysis and Genome-Wide Association Studies (GWAS) have the power to identify variants that capture significant levels of phenotypic variance in complex traits. However, effort and time are required to select the best methods and optimize parameters and pre-processing steps. Although machine learning approaches have been shown to greatly assist in optimization and data processing, applying them to QTL analysis and GWAS is challenging due to the complexity of large, heterogenous datasets. Here, we describe proof-of-concept for an automated machine learning approach, AutoQTL, with the ability to automate many complicated decisions related to analysis of complex traits and generate solutions to describe relationships that exist in genetic data. Results Using a publicly available dataset of 18 putative QTL from a large-scale GWAS of body mass index in the laboratory rat, Rattus norvegicus, AutoQTL captures the phenotypic variance explained under a standard additive model. AutoQTL also detects evidence of non-additive effects including deviations from additivity and 2-way epistatic interactions in simulated data via multiple optimal solutions. Additionally, feature importance metrics provide different insights into the inheritance models and predictive power of multiple GWAS-derived putative QTL. Conclusions This proof-of-concept illustrates that automated machine learning techniques can complement standard approaches and have the potential to detect both additive and non-additive effects via various optimal solutions and feature importance metrics. In the future, we aim to expand AutoQTL to accommodate omics-level datasets with intelligent feature selection and feature engineering strategies.

Background: The human calvaria harbors a variety of pathology and majority of them are incidentally noticed as painless swelling. The aim of the present study is to describe the histopathological subtypes of calvarial lesions, their management and factors affecting their surgical outcome at a tertiary care referral center., Material and Methods: All patients who underwent excision of the calvarial lesions over the last 15 years (from January 2005 to July 2019) were included in this study. Patients having calvarial pathology of infective origin and recurrent lesions were excluded. Any patient with multiple calvarial lesions who have been operated more than one time for same histopathological diagnosis was counted as one patient. We studied Karnofsky Performance Status (KPS) scores and radiological changes at 3-month follow up., Results: Total 65 patients were recruited in this retrospective observational study. The median age of patients in the study was 29 years (range: 8 years to 68 years). Fibrous dysplasia 20 (30.7%) was the commonest lesion while metastatic thyroid carcinoma 3 (4.6%) was the most common malignant pathology. Complete excision was performed in 51 (78.5%) of patients while in 14 (21.5%) cases, subtotal or near total decompression were achieved. After three months of surgery, there was significant improvement in the KPS score (P < 0.00001). Duration of follow up ranges from 6 months to 5 years with 4 mortality in the study., Conclusions: Most of the calvarial tumors were benign and surgically addressable. The malignant lesions were scattered with diverse underlying pathology and required individualized holistic approach., Competing Interests: None

Background  Among the patients of drug-resistant epilepsy, a subset which has focal impaired seizures localizes to the temporal lobe region (TLE). A majority of these cases are surgically amenable with anterior-medial temporal lobe resection or "lesionectomy." Objective  In India, there is scarcity of "specialized centers" providing "comprehensive epilepsy care" and this dearth is further worse in populous states. In this article, we share our single center, observational, and retrospective experience of TLE in background of limited resources and utmost requirement. Methodology  Our study is a retrospective analysis medically refractory epilepsy patients (2016-2019). Patients with medically refractory epilepsy were selected based upon our noninvasive protocol (clinical semiology, interictal scalp electroencephalography (EEG), long-term video EEG monitoring data, and magnetic resonance injury [MRI]). The follow-up was noted from the last out-patient visit record or through telephonic conversation (International League Against Epilepsy score). Results  Of 23 cases of TLE ( n = 7, mesial temporal sclerosis; n = 16 temporal lobe like cavernomas, tumors, or arterio-venous malformations). Single photon emission computed tomography/positron emission tomography (SPECT/PET) was performed in five cases (three cases of ictal/interictal SPECT and two cases of PET scan) where there was discordance between EEG/clinical and MRI. The median follow-up was of 19 months with 18 cases being seizure free. Five cases were fully off the antiepileptic drug (AEDs) while in 15 cases, the AEDs dosages or the number were reduced. Average number of AEDs reduced from 2.9 in preoperative period to 1.2 postoperatively. Two cases had quadrantanopia and one case of cerebrospinal fluid leak. Conclusion  A multidisciplinary and holistic approach is required for best patient care. The results of our initial surgical experience are encouraging., Competing Interests: Conflict of Interest None declared., (Association for Helping Neurosurgical Sick People. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.).)

Background: Pineal region tumors often present with hydrocephalus. Endoscopic third ventriculostomy (ETV) and simultaneous tumor biopsy remain a minimally invasive procedure offering both diagnostic and therapeutic advantages in the management of these tumors. However, different operative techniques have been described in the literature., Aim: The aim is to study the ETV success rate, diagnostic rate of simultaneous tumor biopsy, complications, and follow-up of patients of pineal region tumors managed with ETV and simultaneous tumor biopsy using the single burr hole technique., Methods: The study was performed by retrospectively reviewing the records of patients of pineal region tumors managed by simultaneous ETV and tumor biopsy using a "single burr hole" technique from January 2012 to December 2019., Results: Thirty-four patients (22 males and 12 females) with a mean age of 28.7 years were analyzed. ETV was successful in relieving hydrocephalus in 29 (87.8%) patients. Three patients needed a ventriculoperitoneal shunt, and one required Ommaya reservoir placement for persistent hydrocephalus. Histological diagnosis was successfully established in 26 (78.8%) patients. There were two procedure-related mortalities. Two patients underwent craniotomy and tumor excision subsequently. Radiotherapy was given to 11 patients, and 9 patients were managed by observation alone. The mean follow-up of our study was 15.8 months., Conclusions: Simultaneous ETV and tumor biopsy using a single burr hole technique is a safe, minimally invasive procedure for the management of pineal region tumors., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Asian Journal of Neurosurgery.)

Background: Epidermoids account for <1.5% of all intracranial tumors. Overall, the cerebellopontine angle has been the most commonly reported location. In the supratentorial compartment, epidermoids will usually be found in the suprasellar area, sylvian fissure, and intraventricular area. The interhemispheric fissure represents an extremely rare location for supratentorial epidermoids, with limited cases reported previously. Surgery of an interhemispheric epidermoid can be challenging because of its adherence to the anterior cerebral artery branches or the brain parenchyma itself. In the present study, we have reported the largest Series of interhemispheric epidermoid tumors to better understand the clinical behavior, radiological features, and surgical outcomes., Methods: In the present study, we retrospectively evaluated the data from 22 consecutive patients with interhemispheric epidermoids treated surgically during the past 10 years (2009-2019) at our center. During the same study period, we had treated 2355 patients with brain tumors (both primary and secondary), including 262 patients with intracranial epidermoids. Therefore, interhemispheric epidermoids comprised 0.009% of all brain tumors and 8.4% of all intracranial epidermoids in our experience. These patients all had newly diagnosed tumors and had undergone surgery for the first time at our center. All surgical specimens had been confirmed histopathologically., Results: The mean age of the patients was 31 years (range, 17-61 years), with a male predilection. Seizures and headache were the most common mode of presentation. The average tumor size was 5.2 cm (range, 3.5-10 cm). Of the 22 tumors, 21 were in the anterior two thirds of the fissure. Anatomical distortion of the corpus callosum was seen in 13 patients (59%). The extent of excision was total in 17 (77.3%), near total in 3 (13.6%), and subtotal in 2 (9%) patients. The near or subtotal excisions had been necessary because of either tumor adherence to the pericallosal artery (n = 3) or a missed tumor lobule (n = 2). The mean follow-up time was 32 months, with no tumor recurrence., Conclusion: Interhemispheric epidermoids can often reach a large size with substantial lateral extension found at diagnosis. The position of the anterior cerebral Artery branches can help to differentiate interhemispheric epidermoids from radiologically similar corpus callosum, velum interpositum, and cavum septum pellucidum epidermoids. Complete surgical excision with minimal complications is feasible, with good long-term outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Insular high-grade gliomas are uncommon and constitute approximately 10% of all intracranial high-grade gliomas. Several publications in the recent years have thrown substantial light in the understanding of insular low-grade gliomas. However, there is a paucity of information concerning the spectrum of high-grade lesions affecting the insula, the mode of presentation vis-à-vis low-grade gliomas, and the survival rates to modern therapy., Aims and Objectives: We aim to highlight various clinical patterns, histo-pathological spectrum and the survival rates in patients with high-grade insular lesions. Also, we explore the factors that govern favourable outcomes., Materials and Methods: A retrospective study of 41 patients operated for high-grade insular tumors at our institute between March 2010 to December 2018 was done to evaluate the clinico-radiological features, surgical nuances, survival rates and seizure outcomes., Results: Raised intracranial pressure was the most frequent clinical presentation ( n =28/41, 68.3%). Nearly 60% of the patients ( n =25) had involvement of all four Berger-Sanai zones. The high-grade tumors encountered in our series were: glioblastoma ( n =15), gliosarcoma ( n =3), and embryonal tumor, not otherwise specified in 3 patients, while 21 patients had grade 3 astrocytoma. 33 out of 41 patients (80.5%) in our study showed excellent seizure control (ILAE grade 1A) at follow-up. Clinical presentation with seizures ( P = 0.01, HR=0.3), WHO grade IV histopathology ( P = 0.04, HR=3.7) and development of recurrence ( P = 0.05, HR=5.5) were found to be independent predictors of OS., Conclusion: Insular high-grade gliomas are commoner than thought and nearly half of these are grade IV tumors (51%). A presentation with seizures may indicate precursor low-grade gliomas and portend a better survival. A maximum "safe" surgical resection, keeping the postoperative quality of life in mind, should be the goal., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Asian Journal of Neurosurgery.)

Background: Ependymomas are common intramedullary spinal tumors but there are scattered reports of this tumor presenting with exophytic growth patterns masquerading as intradural extramedullary (IDEM) tumors. Such IDEM ependymomas are seldom suspected preoperatively and it is only during surgery that their existence is revealed. Little is known of such rare growth patterns of an otherwise common intramedullary spinal cord tumor, their characteristics, and their management considerations., Methods: We present a case of an exophytic dorsal ependymoma with a stalk like attachment to the spinal cord and the surgical management in a 24-year old woman. An extensive literature search was carried out on all prominent databases to find out similar cases reported earlier. We excluded filum/conus ependymoma, purely extradural spinal ependymoma as well as the extraspinal ependymomas. Details of each case reported before were obtained and tabulated., Results: IDEM ependymomas have been reported in 54 patients so far, including the present case. Four patterns of growth emerged from the literature review: intramedullary ependymoma with exophytic component (group I, n = 9), exophytic IDEM ependymoma without intramedullary component (group II, n = 6), IDEM ependymoma arising from nerve roots (group III, n = 7), and pure IDEM ependymoma (group IV, n = 32). Except in group I, IDEM ependymoma affects females more frequently, without any specific age predilection. Thoracic spinal cord/canal is the most common location across all groups. Multifocal disease, craniospinal dissemination, and recurrences tend to be maximum in group IV., Conclusions: IDEM ependymomas are more common in thoracic segment of the cord and broadly divisible into 4 subgroups. We suggest a subpial origin of group II IDEM ependymomas. We also advocate proliferation index estimation in grade II ependymomas to enable formulation of an optimal management plan., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mucormycosis of the central nervous system is an uncommon infection caused by saprophytic or parasitic fungi of the subphylum Mucormycotina and order Mucorales viz. Rhizopus, Mucor, and Rhizomucor. Isolated, chronic involvement of the central nervous system is a rare occurrence. To the best of our knowledge, isolated chronic ventricular involvement in an infant has not been reported previously. Isolated intracerebral mucormycosis is a disease of the immunocompromised patient, and to date only 6 cases have been reported in immunocompetent patients, including 2 pediatric cases., Case Description: We present the case of an immunocompetent infant presenting with features of increased intracranial tension. He underwent cerebrospinal fluid diversion and was found to harbor mucormycosis on histopathologic examination of intraventricular debris. We also present a brief review of the relevant literature., Conclusions: Although mucormycosis is an acute fulminant infection, chronic isolated cerebral cases are known in the immunocompetent patient. Patients also may present with isolated hydrocephalus, and hence fungal infection must be ruled out in all, especially if a shunt is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction and Study Design: Spinal arachnoid cyst is an uncommon entity, presenting with radiculopathy or paraparesis. These cysts are usually found in intradural extramedullary region; and the extradural region is a rare location. The exact pathogenesis in the existence of these cysts in the extradural region is still debated. In this article, we have retrospectively analyzed the clinical profile of the rare extradural arachnoid cyst (EDAC)., Methodology: In this study, 19 patients of EDAC operated at our institute between January 2006 to June 2016 are analyzed. All patients with the Oswestry disability index score of >20 were managed surgically (open laminectomy and cyst excision). The clinical outcome was assessed at using 5-point satisfaction scale and McCormick grading., Results: All 13 operated patients had EDACs with communication with the intradural compartment. In 11 (84.6%) patients, cyst wall was excised completely, in 2 (15.3%) patients underwent partial excision of cyst wall; dural communication was closed in all patients ( n = 13). None of the patients had clinical deterioration or radiological recurrence till the last follow-up. Mean follow-up was 52.2 months (range 1-160); all patients were satisfied after surgery (median score was 3)., Discussion: Symptomatic EDACs account <2% of all spinal tumors. The EDACs have communication with the intradural compartment. In our article, we have discussed the approach and management of EDAC, including minimally invasive percutaneous procedures., Conclusion: One should aim for preoperative or intraoperative localization of dural communication and try to disconnect the extradural cyst from the intradural connection to prevent recurrence. Surgical treatment is complete excision of the cyst., Competing Interests: There are no conflicts of interest.