cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5120785.v1
title: Supplementary Material for: A Case for the Worldwide Collection of Primary Benign Brain Tumors

description: <i>Background:</i> Incidence data on malignant tumors are reported by the International Agency for Research on Cancer, with 189,485 new malignant brain tumors globally in 2002. However, collection and reporting of benign brain tumors are not universal. The objective here is to encourage the collection of primary benign brain tumors worldwide. <i>Methods:</i> Worldwide numbers of primary benign brain tumors were estimated through published articles and cancer registry reports presenting directly or indirectly reported benign incidence rates or frequencies for regions or countries. <i>Results:</i> An estimated 186,678 benign brain tumors were diagnosed worldwide in 2002. The estimated numbers of benign brain tumors were higher in females than males (105,918 vs. 80,759). Since many countries do not report primary benign brain tumors, the incidence rate estimates vary significantly by region. <i>Conclusions:</i> This is the first survey to assess worldwide numbers of benign brain tumors. Under-reporting, non-standardized collection, lack of age-adjustment, and other causes of the varying incidence rates must be considered. However, the estimated number of benign brain tumors approximately equals, and could exceed, the number of malignant brain tumors globally. Registration of primary benign brain histologies in different geographical areas and ethnicities could provide clues to the underlying causes of these tumors.
DOI: 10.6084/m9.figshare.5120776
title: Supplementary Material for: A New Method to Account for Missing Data in Case-Parent Triad Studies

description: <i>Background/Aims:</i> The case-parent triad design is commonly used in genetic association studies. Generally, samples are drawn from an affected offspring, manifesting a phenotype of interest, as well as from the parents. The trio genotypes may be analyzed using a variety of available methods, but we focus on log-linear models because they test for genetic association and additionally estimate the relative risks of transmission. The models need to be modified to adjust for missing genotypes. Furthermore, instability in the parameter estimates can arise when certain kinds of genotype combinations do not appear in the dataset. <i>Methods:</i> In this paper, we kill two birds with one stone. We propose a new method to simultaneously account for missing genotype data and genotype combinations with zero counts. This method solves a zero-inflated Poisson (ZIP) regression likelihood. The maximum likelihood estimates yield relative risks and the information matrix gives appropriate variance estimates for inference. A likelihood ratio test determines the significance of genetic association. <i>Results:</i> We compared the ZIP regression to previously proposed methods in both simulation studies and in a dataset that investigates the risk of orofacial clefts. The ZIP likelihood estimates regression coefficients with less bias than other methods when the minor allele frequency is small.
DOI: 10.6084/m9.figshare.5120779.v1
title: Supplementary Material for: A Powerful Two-Stage Association Test Using Case-Control and Case-Parents Genotype Data

description: <i>Objective:</i> The performance of association tests based on case-control or case-parents substudy alone can be improved by jointly using genetic data from two substudies. However, genetic data from different sources may not be combinable due to population stratification. We propose a two-stage association test based on using combinability tests in stage 1 and association tests in stage 2. <i>Methods:</i> The combinability tests are designed for testing that genotype data from different sources have same genotype frequencies and relative risks. The association tests are well known tests in the literature. We propose a method to adjust the significance levels at two stages so that the overall type I error rate of the two-stage test can be controlled at the desired level. <i>Results:</i> The simulation results confirm that the two-stage test has empirical type I error rates approximately equal to the predetermined levels while making substantially fewer false negatives than the usual test based only on case-parents substudy. <i>Conclusion:</i> It is advantageous to combinecase-control and case-parents data into a single analysis.The two-stage test has significant power improvement when the family-based test has weak or moderate power performance and is robust to the effect of population stratification.
DOI: 10.6084/m9.figshare.5120782.v1
title: Supplementary Material for: Dietary Fat and Coronary Heart Disease: Summary of Evidence from Prospective Cohort and Randomised Controlled Trials

description: Medicine
DOI: 10.6084/m9.figshare.5120773
title: Supplementary Material for: Comparison of Different Haplotype-Based Haplotype-Based Association Methods for Gene-Environment (G×E) Interactions in Case-Control Studies when Haplotype-Phase Is Ambiguous

description: <i>Objective:</i> We compared four haplotype-based approaches for the analysis of gene-environment interactions when haplotype-phase is ambiguous. The methods employ different versions of the expectation maximization algorithm and differ in the choice of the reference group and in the way the risk of disease is modeled (retrospective versus prospective). Furthermore, the methods are based on distinct assumptions (such as Hardy Weinberg equilibrium). The haplotype-based methods were also compared to single-marker logistic regression (LR). <i>Methods:</i> We simulated case-control scenarios where the risk variant was directly genotyped (direct scenario) or in linkage disequilibrium with the genotyped markers (indirect scenario). <i>Results:</i> The retrospective methods tended to be more powerful for detecting interactions than the prospective methods. In the indirect scenarios, the power of all methods was decreased. However, the power of the retrospectives methods was high in some scenarios and the interactions may only be detectable when using these approaches. Furthermore, we observed that the precision of one prospective method was clearly lower than the precision of the retrospective methods. <i>Conclusion:</i> For the analysis of gene-environment (G×E) interactions in case-control data, the investigated retrospective methods can be an attractive alternative to haplotype-based methods which do not account for the retrospective sampling design.
DOI: 10.6084/m9.figshare.5120764
title: Supplementary Material for: High-Dose Lovastatin for Acute Ischemic Stroke: Results of the Phase I Dose Escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART)

description: <i>Background:</i> Hydroxymethylglutaryl coenzyme A reductase inhibitors (‘statins’) reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. <i>Methods:</i> We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7–13% toxicity. <i>Results:</i> We enrolled 33 patients (16 men/17 women, age range 23–82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. <i>Conclusions:</i> Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.
DOI: 10.6084/m9.figshare.5120767
title: Supplementary Material for: Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease

description: <i>Objective:</i> A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. <i>Methods:</i> Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. <i>Results:</i> Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. <i>Conclusion:</i> This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants.
DOI: 10.6084/m9.figshare.5120770
title: Supplementary Material for: A New Strategy for Linkage Analysis under Epistasis Taking into Account Genetic Heterogeneity

description: <i>Background/Aims:</i> Epistasis, the biological interaction of multiple genes modulating their individual effects, is likely omnipresent in complex diseases, and modelling epistasis in linkage studies can help detect loci with little marginal effect and detect epistatic effects themselves. We propose a complete three-step strategy for parametric linkage analysis under epistasis and heterogeneity in extended pedigrees. <i>Methods:</i> (1) Loci most likely involved in epistatic interactions are pre-screened using two-locus one-marker analyses. (2) Among selected loci, linkage to each locus is evaluated conditionally on linkage information at another locus under two-locus epistatic models. Linkage statistics are maximized over a space of epistatic models to avoid misspecification of model parameters. (3) Families linked to the conditioning locus are selected to deal with heterogeneity between pairs of epistatically interacting loci and other unlinked loci. Properties of conditional linkage statistics prevent the introduction of bias. <i>Results:</i> Simulations reveal important gains in power to detect a locus with weak marginal effect involved in epistatic interaction. Application of our methods to schizophrenia and bipolar disorder in Eastern Quebec kindreds suggests epistasis between three locus pairs for bipolar disorder: 8p11-16p13, 15q11-16p13 and 18q12-15q11. <i>Conclusion:</i> These results suggest that the proposed strategy is powerful for tackling complex phenotypes involving epistasis and heterogeneity.
DOI: 10.6084/m9.figshare.5120773.v1
title: Supplementary Material for: Comparison of Different Haplotype-Based Haplotype-Based Association Methods for Gene-Environment (G×E) Interactions in Case-Control Studies when Haplotype-Phase Is Ambiguous

description: <i>Objective:</i> We compared four haplotype-based approaches for the analysis of gene-environment interactions when haplotype-phase is ambiguous. The methods employ different versions of the expectation maximization algorithm and differ in the choice of the reference group and in the way the risk of disease is modeled (retrospective versus prospective). Furthermore, the methods are based on distinct assumptions (such as Hardy Weinberg equilibrium). The haplotype-based methods were also compared to single-marker logistic regression (LR). <i>Methods:</i> We simulated case-control scenarios where the risk variant was directly genotyped (direct scenario) or in linkage disequilibrium with the genotyped markers (indirect scenario). <i>Results:</i> The retrospective methods tended to be more powerful for detecting interactions than the prospective methods. In the indirect scenarios, the power of all methods was decreased. However, the power of the retrospectives methods was high in some scenarios and the interactions may only be detectable when using these approaches. Furthermore, we observed that the precision of one prospective method was clearly lower than the precision of the retrospective methods. <i>Conclusion:</i> For the analysis of gene-environment (G×E) interactions in case-control data, the investigated retrospective methods can be an attractive alternative to haplotype-based methods which do not account for the retrospective sampling design.
DOI: 10.6084/m9.figshare.5120776.v1
title: Supplementary Material for: A New Method to Account for Missing Data in Case-Parent Triad Studies

description: <i>Background/Aims:</i> The case-parent triad design is commonly used in genetic association studies. Generally, samples are drawn from an affected offspring, manifesting a phenotype of interest, as well as from the parents. The trio genotypes may be analyzed using a variety of available methods, but we focus on log-linear models because they test for genetic association and additionally estimate the relative risks of transmission. The models need to be modified to adjust for missing genotypes. Furthermore, instability in the parameter estimates can arise when certain kinds of genotype combinations do not appear in the dataset. <i>Methods:</i> In this paper, we kill two birds with one stone. We propose a new method to simultaneously account for missing genotype data and genotype combinations with zero counts. This method solves a zero-inflated Poisson (ZIP) regression likelihood. The maximum likelihood estimates yield relative risks and the information matrix gives appropriate variance estimates for inference. A likelihood ratio test determines the significance of genetic association. <i>Results:</i> We compared the ZIP regression to previously proposed methods in both simulation studies and in a dataset that investigates the risk of orofacial clefts. The ZIP likelihood estimates regression coefficients with less bias than other methods when the minor allele frequency is small.
DOI: 10.6084/m9.figshare.5120767.v1
title: Supplementary Material for: Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease

description: <i>Objective:</i> A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. <i>Methods:</i> Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. <i>Results:</i> Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. <i>Conclusion:</i> This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants.
DOI: 10.6084/m9.figshare.5120761
title: Supplementary Material for: Torticollis under Cyclobenzaprine

description: The muscle-relaxing 5-HT<sub>2</sub> receptor antagonist cyclobenzaprine is structurally closely related to amitriptyline. It is widely used to treat patients presenting with back pain and fibromyalgia. Very rarely cyclobenzaprine toxicity can result in extrapyramidal symptoms, but occurrence of torticollis has not been reported so far. We report on a patient presenting with torticollis and myoclonic movements after treatment with cyclobenzaprine, who was successfully treated with intravenous biperiden. This case might be additional evidence for the necessity of appropriate dosage in case of liver impairment. Secondly there are possibly consequences as regards the therapy of motor side effects.
DOI: 10.6084/m9.figshare.5120770.v1
title: Supplementary Material for: A New Strategy for Linkage Analysis under Epistasis Taking into Account Genetic Heterogeneity

description: <i>Background/Aims:</i> Epistasis, the biological interaction of multiple genes modulating their individual effects, is likely omnipresent in complex diseases, and modelling epistasis in linkage studies can help detect loci with little marginal effect and detect epistatic effects themselves. We propose a complete three-step strategy for parametric linkage analysis under epistasis and heterogeneity in extended pedigrees. <i>Methods:</i> (1) Loci most likely involved in epistatic interactions are pre-screened using two-locus one-marker analyses. (2) Among selected loci, linkage to each locus is evaluated conditionally on linkage information at another locus under two-locus epistatic models. Linkage statistics are maximized over a space of epistatic models to avoid misspecification of model parameters. (3) Families linked to the conditioning locus are selected to deal with heterogeneity between pairs of epistatically interacting loci and other unlinked loci. Properties of conditional linkage statistics prevent the introduction of bias. <i>Results:</i> Simulations reveal important gains in power to detect a locus with weak marginal effect involved in epistatic interaction. Application of our methods to schizophrenia and bipolar disorder in Eastern Quebec kindreds suggests epistasis between three locus pairs for bipolar disorder: 8p11-16p13, 15q11-16p13 and 18q12-15q11. <i>Conclusion:</i> These results suggest that the proposed strategy is powerful for tackling complex phenotypes involving epistasis and heterogeneity.
DOI: 10.6084/m9.figshare.5120755
title: Supplementary Material for: Efficacy and Safety of Mistletoe Preparations (Viscum album) for Patients with Cancer Diseases

description: <i>Background: </i>Mistletoe is often used as a complementary approach in oncology. Despite experimental anti-tumour effects and several reviews there remains controversy about its clinical role. <i>Patients and Methods: </i>Potentially relevant trials were identified to perform a systematic review (databases: e.g. EMBASE, MEDLINE; hand search: e.g. bibliographies; search terms: e.g. mistletoe). To be included, randomised or comparative clinical trials at least had to examine mistletoe preparations standardized according to manufacturing process and to describe interventions explicitly. Additionally, cohort studies were included for reasons of external validity. Results were summarised in tables. <i>Results: </i>18 clinical trials (&gt;6,800 participants) were included. Their internal quality was mostly low. Due to heterogeneity between trials a meta-analysis was impossible. Regarding efficacy, findings were inconsistent regarding life expectancy, relation to tumour entity, dosing and treatment duration. Yet, studies indicate that quality of life (QoL) is improved. As these findings do not seem to be limited to one of the different parenteral mistletoe preparations reviewed the treatment may be summarised under the umbrella term ‘mistletoe therapy’. Regarding safety, 1 serious adverse event (AE) related to mistletoe was described; non-serious AEs were local reactions at injection site. Allergic reactions were rare. <i>Conclusion: </i>Supportive ‘mistletoe therapy’ seems safe and beneficial for QoL in adult patients with solid tumours. But there is an urgent need to confirm its efficacy in patient-centred care in a complex oncological setting. This has to be evaluated systematically in prospective observational trials with validated, multidimensional patient-rated QoL questionnaires and comparisons of different preparations and dosages.
DOI: 10.6084/m9.figshare.5120758
title: Supplementary Material for: Extraction of a Chronically Implanted, Microfabricated, Subretinal Electrode Array

description: <i>Purpose:</i> To assess the feasibility of extraction of a chronically implanted subretinal electrode array. <i>Methods:</i> Inactive, polyimide strips (10 mm × 1.5 mm × 15 μm) were surgically implanted into the subretinal space of 8 rabbits using a mostly ab externo approach. Pre- and postoperative clinical examinations, electroretinography and in some cases optical coherence tomography were performed to follow the course of the eyes. Two months after implantation, the polyimide strips were extracted from 5 eyes; 2 animals kept the implants and served as controls. All animals were then sacrificed and eyes enucleated for histological examination. <i>Results:</i> All 8 surgeries yielded successful placement of the arrays into the subretinal space. All 5 extraction surgeries were performed without obvious complications. Clinical examinations and electroretinography did not reveal any significant abnormalities. The histological examinations showed alterations from normal anatomy in all animals; the anatomical changes in the explanted animals were relatively mild and confined to the area of the surgery. <i>Conclusions:</i> Successful extraction of electrode arrays from the subretinal space of rabbits can be reliably performed 2 months after implantation, which is beyond the time period when postoperative scarring would be most intense.
DOI: 10.6084/m9.figshare.5120761.v1
title: Supplementary Material for: Torticollis under Cyclobenzaprine

description: The muscle-relaxing 5-HT<sub>2</sub> receptor antagonist cyclobenzaprine is structurally closely related to amitriptyline. It is widely used to treat patients presenting with back pain and fibromyalgia. Very rarely cyclobenzaprine toxicity can result in extrapyramidal symptoms, but occurrence of torticollis has not been reported so far. We report on a patient presenting with torticollis and myoclonic movements after treatment with cyclobenzaprine, who was successfully treated with intravenous biperiden. This case might be additional evidence for the necessity of appropriate dosage in case of liver impairment. Secondly there are possibly consequences as regards the therapy of motor side effects.