Cognitive impairment in patients with bipolar disorder (BD) is not restricted to symptomatic phases. It is also present in euthymia. There is evidence of differences in the brain’s structure between bipolar patients and healthy individuals, as well as changes over time in patients. Lithium constitutes the gold standard in long-term prophylactic treatment. Appropriate therapy that prevents new episodes improves the disease’s course and reduces the frequency of harmful outcomes. Interestingly, preclinical data suggest that lithium has a (additional) neuroprotective effect. There is limited data on its related effects in humans and even less on its long-term application. In this multi-center cross-sectional study from the International Group for the Study of Lithium-treated Patients (IGSLi), we compared three groups: bipolar patients without long-term lithium treatment (non-Li group; <3 months cumulative lithium exposure, ≥24 months ago), bipolar patients with long-term lithium treatment (Li group, ongoing treatment ≥24 months), and healthy subjects (controls). Strict inclusion and exclusion criteria were defined; the inclusion criteria for patients were diagnosis of BD types I or II, duration of illness ≥10 years, ≥5 episodes in patient’s history and a euthymic mood state. Neurocognitive functioning was assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the California Verbal Learning Test (CVLT), and a visual backward masking (VBM) task. A total of 142 subjects were included, 31 in the non-Li and 58 in the Li group, as well as 53 healthy controls. Treated patients with long-standing BD and controls did not differ significantly in overall cognitive functioning and verbal learning, recall, and recognition; regardless of whether lithium had been part of the treatment. Patients, however, demonstrated poorer early visual information processing than healthy controls, with the lithium-treated patients performing worse than those without. Our data suggest that bipolar patients with a long illness history and effective prophylactic treatment do not reveal significantly impaired general cognitive functioning or verbal learning and memory. However, they are worse at processing early visual information. Accompanying volumetric and spectroscopic data suggest cell loss in patients not treated with lithium that may be counterbalanced by long-term lithium treatment.
Lithium; Bipolar disorder; Cognition
Gene Ontology (GO) provides dynamic controlled vocabularies to aid in the description of the functional biological attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org). Here we describe collaboration between the renal biomedical research community and the GO Consortium to improve the quality and quantity of GO terms describing renal development. In the associated annotation activity, the new and revised terms were associated with gene products involved in renal development and function. This project resulted in a total of 522 GO terms being added to the ontology and the creation of approximately 9,600 kidney-related GO term associations to 940 UniProt Knowledgebase (UniProtKB) entries, covering 66 taxonomic groups. We demonstrate the impact of these improvements on the interpretation of GO term analyses performed on genes differentially expressed in kidney glomeruli affected by diabetic nephropathy. In summary, we have produced a resource that can be utilized in the interpretation of data from small- and large-scale experiments investigating molecular mechanisms of kidney function and development and thereby help towards alleviating renal disease.
The Gene Ontology Consortium (GOC) is a major bioinformatics project that provides structured controlled vocabularies to classify gene product function and location. GOC members create annotations to gene products using the Gene Ontology (GO) vocabularies, thus providing an extensive, publicly available resource. The GO and its annotations to gene products are now an integral part of functional analysis, and statistical tests using GO data are becoming routine for researchers to include when publishing functional information. While many helpful articles about the GOC are available, there are certain updates to the ontology and annotation sets that sometimes go unobserved. Here we describe some of the ways in which GO can change that should be carefully considered by all users of GO as they may have a significant impact on the resulting gene product annotations, and therefore the functional description of the gene product, or the interpretation of analyses performed on GO datasets. GO annotations for gene products change for many reasons, and while these changes generally improve the accuracy of the representation of the underlying biology, they do not necessarily imply that previous annotations were incorrect. We additionally describe the quality assurance mechanisms we employ to improve the accuracy of annotations, which necessarily changes the composition of the annotation sets we provide. We use the Universal Protein Resource (UniProt) for illustrative purposes of how the GO Consortium, as a whole, manages these changes.
Gene Ontology; Annotation; Function prediction; Misinterpretation
UniProtKB/Swiss-Prot provides expert curation with information extracted from literature and curator-evaluated computational analysis. As knowledgebases continue to play an increasingly important role in scientific research, a number of studies have evaluated their accuracy and revealed various errors. While some are curation errors, others are the result of incorrect information published in the scientific literature. By taking the example of sirtuin-5, a complex annotation case, we will describe the curation procedure of UniProtKB/Swiss-Prot and detail how we report conflicting information in the database. We will demonstrate the importance of collaboration between resources to ensure curation consistency and the value of contributions from the user community in helping maintain error-free resources.
Introduction: Gender dysphoria (GD) is a condition in which there is a marked incongruence between an individual’s psychological perception of his/her sex and their biological phenotype. Gender identity disorder was officially renamed “gender dysphoria” in the DSM-V in 2013. The prevalence and demographics of GD vary according to geographical location and has not been well-documented in Ireland.
Methods: We retrospectively reviewed medical records of 218 patients with suspected or confirmed GD referred to our endocrine service for consideration of hormonal therapy (HT) between 2005 and early 2014. We documented their demographics, clinical characteristics, and treatment during the study period.
Results: The prevalence of GD in the Irish population was 1:10,154 male-to-female (MTF) and 1:27,668 female-to-male (FTM), similar to reported figures in Western Europe. 159 of the patients were MTF and 59 were FTM, accounting for 72.9% and 27.1% of the cohort, respectively. The rate of referral has increased year-on-year, with 55 patients referred in 2013 versus 6 in 2005. Mean ages were 32.6 years (MTF) and 32.2 years (FTM). 22 of the patients were married and 41 had children, with 2 others having pregnant partners. 37.6% were referred by a psychologist, with the remainder evenly divided between GPs and psychiatric services. There were low rates of coexistent medical illness although psychiatric conditions were more prevalent, depression being a factor in 34.4% of patients. 5.9% of patients did not attend a mental health professional. 74.3% are currently on HT, and 9.17% have had gender reassignment surgery (GRS). Regret following hormonal or surgical treatment was in line with other Western European countries (1.83%).
Conclusion: The incidence of diagnosis and referral of GD in Ireland is increasing. This brings with it multiple social, health, and financial implications. Clear and accessible treatment pathways supported by mental health professionals is essential.
gender dysphoria; gender identity disorder; transgender; gender reassignment surgery; gonadectomy; hormone therapy
Experimental data exists for only a vanishingly small fraction of sequenced microbial genes. This community page discusses the progress made by the COMBREX project to address this important issue using both computational and experimental resources.
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods
Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
While indicated for schizophrenia and acute mania, ziprasidone’s evidence base and use in clinical practice extends beyond these regulatory approvals. We, an invited panel of experts led by a working group of 3, critically examined the evidence and our collective experience regarding the effectiveness, tolerability and safety of ziprasidone across its clinical uses. There was no opportunity for manufacturer input into the content of the review. As anticipated, ziprasidone was found to be effective for its indicated uses, although its utility in mania and mixed states lacked comparative data. Beyond these uses, the available data were either unimpressive or were lacking. An attractive characteristic is its neutral effect on weight thereby providing patients with a non-obesogenic long-term treatment option. Key challenges in practice include the need for dosing on a full stomach and managing its early onset adverse effect of restlessness. Addressing these issues are critical to its long-term success
Ziprasidone; Expert consensus; Schizophrenia; Bipolar disorder; Depression; Anxiety; Dosing; Off-label
The Gene Ontology (GO) is the de facto standard for the functional description of gene products, providing a consistent, information-rich terminology applicable across species and information repositories. The UniProt Consortium uses both manual and automatic GO annotation approaches to curate UniProt Knowledgebase (UniProtKB) entries. The selection of a protein set prioritized for manual annotation has implications for the characteristics of the information provided to users working in a specific field or interested in particular pathways or processes. In this article, we describe an organelle-focused, manual curation initiative targeting proteins from the human peroxisome. We discuss the steps taken to define the peroxisome proteome and the challenges encountered in defining the boundaries of this protein set. We illustrate with the use of examples how GO annotations now capture cell and tissue type information and the advantages that such an annotation approach provides to users.
http://www.ebi.ac.uk/GOA/ and http://www.uniprot.org
Several studies have reported higher prevalence of obesity in patients suffering from bipolar disorder (BD). To study the relation of elevated body mass index (BMI) in patients with BD more closely, we investigated differences in sociodemographic, clinical, and medical characteristics with respect to BMI, with the hypothesis that BMI is related to prognosis and outcome.
We measured the BMI of 276 subjects of a tertiary care sample from the Maritime Bipolar Registry. Subjects were 16 to 83 years old, with psychiatric diagnoses of bipolar I disorder (n = 186), bipolar II disorder (n = 85), and BD not otherwise specified (n = 5). The registry included basic demographic data and details of the clinical presentation. We first examined the variables showing a significant association with BMI; subsequently, we modeled the relationship between BMI and psychiatric outcome using structural equation analysis.
The prevalence of obesity in our sample was 39.1%. We found higher BMI in subjects with a chronic course (p < 0.001) and longer duration of illness (p = 0.02), lower scores on the Global Assessment of Functioning Scale (p = 0.02), and on disability (p = 0.002). Overweight patients had more frequent comorbid subthreshold social (p = 0.02) and generalized anxiety disorders (p = 0.05), diabetes mellitus type II (p < 0.001), and hypertension (p = 0.001). Subjects who achieved complete remission of symptoms on lithium showed significantly lower BMI (p = 0.01).
Our findings suggest that BMI is associated with the prognosis and outcome of BD. Whether this association is causal remains to be determined.
PMID: 19689507 CAMSID: cams2668
bipolar disorder; body mass index; BMI; clinical characteristics; clinical correlates; clinical course; comorbidity; obesity
Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li).
We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15–30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction.
The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls.
Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients without Li exposure, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.
PMID: 22548899 CAMSID: cams2505
bipolar disorders; hippocampus; illness burden; lithium; neuroprotection
Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.
Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.
The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= −4.724, 95% CI: −8.124 to −1.323, p = 0.006), controlling for each country’s median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.
The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.
PMID: 22612720 CAMSID: cams2451
age of onset; bipolar disorder; solar insolation; sunlight
The Structure Integration with Function, Taxonomy and Sequences resource (SIFTS; http://pdbe.org/sifts) is a close collaboration between the Protein Data Bank in Europe (PDBe) and UniProt. The two teams have developed a semi-automated process for maintaining up-to-date cross-reference information to UniProt entries, for all protein chains in the PDB entries present in the UniProt database. This process is carried out for every weekly PDB release and the information is stored in the SIFTS database. The SIFTS process includes cross-references to other biological resources such as Pfam, SCOP, CATH, GO, InterPro and the NCBI taxonomy database. The information is exported in XML format, one file for each PDB entry, and is made available by FTP. Many bioinformatics resources use SIFTS data to obtain cross-references between the PDB and other biological databases so as to provide their users with up-to-date information.
The availability of comprehensive information about enzymes plays an important role in answering questions relevant to interdisciplinary fields such as biochemistry, enzymology, biofuels, bioengineering and drug discovery. At the EMBL European Bioinformatics Institute, we have developed an enzyme portal (http://www.ebi.ac.uk/enzymeportal) to provide this wealth of information on enzymes from multiple in-house resources addressing particular data classes: protein sequence and structure, reactions, pathways and small molecules. The fact that these data reside in separate databases makes information discovery cumbersome. The main goal of the portal is to simplify this process for end users.
The 5th International Biocuration Conference brought together over 300 scientists to exchange on their work, as well as discuss issues relevant to the International Society for Biocuration’s (ISB) mission. Recurring themes this year included the creation and promotion of gold standards, the need for more ontologies, and more formal interactions with journals. The conference is an essential part of the ISB's goal to support exchanges among members of the biocuration community. Next year's conference will be held in Cambridge, UK, from 7 to 10 April 2013. In the meanwhile, the ISB website provides information about the society's activities (http://biocurator.org), as well as related events of interest.
Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity.
To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy.
We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t41 = −3.44, corrected p < 0.01) or control participants (t35 = −2.91, corrected p < 0.05), who did not differ from the Li group (t46 = −0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = −0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74).
Study limitations include the cross-sectional design and exposure to other medications.
Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.
As the deluge of genomic DNA sequence grows the fraction of protein sequences that have been manually curated falls. In turn, as the number of laboratories with the ability to sequence genomes in a high-throughput manner grows, the informatics capability of those labs to accurately identify and annotate all genes within a genome may often be lacking. These issues have led to fears about transitive annotation errors making sequence databases less reliable. During the lifetime of the Pfam protein families database a number of protein families have been built, which were later identified as composed solely of spurious open reading frames (ORFs) either on the opposite strand or in a different, overlapping reading frame with respect to the true protein-coding or non-coding RNA gene. These families were deleted and are no longer available in Pfam. However, we realized that these may perform a useful function to identify new spurious ORFs. We have collected these families together in AntiFam along with additional custom-made families of spurious ORFs. This resource currently contains 23 families that identified 1310 spurious proteins in UniProtKB and a further 4119 spurious proteins in a collection of metagenomic sequences. UniProt has adopted AntiFam as a part of the UniProtKB quality control process and will investigate these spurious proteins for exclusion.
Curated databases are an integral part of the tool set that researchers use on a daily basis for their work. For most users, however, how databases are maintained, and by whom, is rather obscure. The International Society for Biocuration (ISB) represents biocurators, software engineers, developers and researchers with an interest in biocuration. Its goals include fostering communication between biocurators, promoting and describing their work, and highlighting the added value of biocuration to the world. The ISB recently conducted a survey of biocurators to better understand their educational and scientific backgrounds, their motivations for choosing a curatorial job and their career goals. The results are reported here. From the responses received, it is evident that biocuration is performed by highly trained scientists and perceived to be a stimulating career, offering both intellectual challenges and the satisfaction of performing work essential to the modern scientific community. It is also apparent that the ISB has at least a dual role to play to facilitate biocurators’ work: (i) to promote biocuration as a career within the greater scientific community; (ii) to aid the development of resources for biomedical research through promotion of nomenclature and data-sharing standards that will allow interconnection of biological databases and better exploit the pivotal contributions that biocurators are making.
The Gene Ontology (GO) resource provides dynamic controlled vocabularies to provide an information-rich resource to aid in the consistent description of the functional attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org). System-focused projects, such as the Renal and Cardiovascular GO Annotation Initiatives, aim to provide detailed GO data for proteins implicated in specific organ development and function. Such projects support the rapid evaluation of new experimental data and aid in the generation of novel biological insights to help alleviate human disease. This paper describes the improvement of GO data for renal and cardiovascular research communities and demonstrates that the cardiovascular-focused GO annotations, created over the past three years, have led to an evident improvement of microarray interpretation. The reanalysis of cardiovascular microarray datasets confirms the need to continue to improve the annotation of the human proteome.
GO annotation data is freely available from: ftp://ftp.geneontology.org/pub/go/gene-associations/
The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360 000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set.
The promise of genome sequencing was that the vast undiscovered country would be mapped out by comparison of the multitude of sequences available and would aid researchers in deciphering the role of each gene in every organism. Researchers recognize that there is a need for high quality data. However, different annotation procedures, numerous databases, and a diminishing percentage of experimentally determined gene functions have resulted in a spectrum of annotation quality. NCBI in collaboration with sequencing centers, archival databases, and researchers, has developed the first international annotation standards, a fundamental step in ensuring that high quality complete prokaryotic genomes are available as gold standard references. Highlights include the development of annotation assessment tools, community acceptance of protein naming standards, comparison of annotation resources to provide consistent annotation, and improved tracking of the evidence used to generate a particular annotation. The development of a set of minimal standards, including the requirement for annotated complete prokaryotic genomes to contain a full set of ribosomal RNAs, transfer RNAs, and proteins encoding core conserved functions, is an historic milestone. The use of these standards in existing genomes and future submissions will increase the quality of databases, enabling researchers to make accurate biological discoveries.
The gene ontology (go) resource provides dynamic controlled vocabularies to aid in the description of the functional attributes and subcellular locations of gene products from all taxonomic groups (www.geneontology.org). A renal-focused curation initiative, funded by Kidney Research UK and supported by the GO Consortium, has started at the European Bioinformatics Institute and aims to provide a detailed GO resource for mammalian proteins implicated in renal development and function. This report outlines the aims of this initiative and explains how the renal community can become involved to help improve the availability, quality and quantity of GO terms and their association to specific proteins.
gene ontology; annotation; biocuration; kidney; renal
The advent of sequencing and structural genomics projects has provided a dramatic boost in the number of protein structures and sequences. Due to the high-throughput nature of these projects, many of the molecules are uncharacterised and their functions unknown. This, in turn, has led to the need for a greater number and diversity of tools and databases providing annotation through transfer based on homology and prediction methods. Though many such tools to annotate protein sequence and structure exist, they are spread throughout the world, often with dedicated individual web pages. This situation does not provide a consensus view of the data and hinders comparison between methods. Integration of these methods is needed. So far this has not been possible since there was no common vocabulary available that could be used as a standard language. A variety of terms could be used to describe any particular feature ranging from different spellings to completely different terms. The Protein Feature Ontology (http://www.ebi.ac.uk/ontology-lookup/browse.do?ontName=BS) is a structured controlled vocabulary for features of a protein sequence or structure. It provides a common language for tools and methods to use, so that integration and comparison of their annotations is possible. The Protein Feature Ontology comprises approximately 100 positional terms (located in a particular region of the sequence), which have been integrated into the Sequence Ontology (SO). 40 non-positional terms which describe general protein properties have also been defined and, in addition, post-translational modifications are described by using an already existing ontology, the Protein Modification Ontology (MOD). The Protein Feature Ontology has been used by the BioSapiens Network of Excellence, a consortium comprising 19 partner sites in 14 European countries generating over 150 distinct annotation types for protein sequences and structures.
The Gene Ontology (GO) has proven to be a valuable resource for functional annotation of gene products. At well over 27 000 terms, the descriptiveness of GO has increased rapidly in line with the biological data it represents. Therefore, it is vital to be able to easily and quickly mine the functional information that has been made available through these GO terms being associated with gene products. QuickGO is a fast, web-based tool for browsing the GO and all associated GO annotations provided by the GOA group. After undergoing a redevelopment, QuickGO is now able to offer many more features beyond simple browsing. Users have responded well to the new tool and given very positive feedback about its usefulness. This tutorial will demonstrate how some of these features could be useful to the researcher wanting to discover more about their dataset, particular areas of biology or to find new ways of directing their research.
Database URL: http://www.ebi.ac.uk/QuickGO