Assessing the use of supplementary materials to improve genomic variant discovery.

The curation of genomic variants requires collecting evidence not only in variant knowledge bases but also in the literature. However, some variants result in no match when searched in the scientific literature. Indeed, it has been reported that a significant subset of information related to genomic variants are not reported in the full text, but only in the supplementary materials associated with a publication. In the study, we present an evaluation of the use of supplementary data (SD) to improve the retrieval of relevant scientific publications for variant curation. Our experiments show that searching SD enables to significantly increase the volume of documents retrieved for a variant, thus reducing by ∼63% the number of variants for which no match is found in the scientific literature. SD thus represent a paramount source of information for curating variants of unknown significance and should receive more attention by global research infrastructures, which maintain literature search engines. Database URL https://www.expasy.org/resources/variomes.

Designing an Optimal Expansion Method to Improve the Recall of a Genomic Variant Curation-Support Service.

The importance of genomic data for health is rapidly growing but accessing and gathering information about variants from different sources is hindered by highly heterogeneous representations of variants, as outlined by clinical associations (AMP/ASCO/CAP) in their recommendations. To enable a smooth and effective retrieval of variant-containing documents from different resources, we developed a tool (https://goldorak.hesge.ch/synvar/) that generates for any given SNP - including variant not present in existing databases - its corresponding description at the genome, transcript and protein levels. It provides variant descriptions in the HGVS format as well as in many non-standard formats found in the literature along with database identifiers. We present the SynVar service and evaluate its impact on the recall of a genomic variant curation-support service. Using SynVar to search variants in the literature enables to increase the recall by +133.8% without a strong impact on precision (i.e. 93%).

Analyzing the Information Content of Text-Based Files in Supplementary Materials of Biomedical Literature.

We present an analysis of supplementary materials of PubMed Central (PMC) articles and show their importance in indexing and searching biomedical literature, in particular for the emerging genomic medicine field. On a subset of articles from PubMed Central, we use text mining methods to extract MeSH terms from abstracts, full texts, and text-based supplementary materials. We find that the recall of MeSH annotations increases by about 5.9 percentage points (+20% on relative percentage) when considering supplementary materials compared to using only abstracts. We further compare the supplementary material annotations with full-text annotations and we find out that the recall of MeSH terms increases by 1.5 percentage point (+3% on relative percentage). Additionally, we analyze genetic variant mentions in abstracts and full-texts and compare them with mentions found in supplementary text-based files. We find that the majority (about 99%) of variants are found in text-based supplementary files. In conclusion, we suggest that supplementary data should receive more attention from the information retrieval community, in particular in life and health sciences.

Variomes: a high recall search engine to support the curation of genomic variants.

MOTIVATION: Identification and interpretation of clinically actionable variants is a critical bottleneck. Searching for evidence in the literature is mandatory according to ASCO/AMP/CAP practice guidelines; however, it is both labor-intensive and error-prone. We developed a system to perform triage of publications relevant to support an evidence-based decision. The system is also able to prioritize variants. Our system searches within pre-annotated collections such as MEDLINE and PubMed Central. RESULTS: We assess the search effectiveness of the system using three different experimental settings: literature triage; variant prioritization and comparison of Variomes with LitVar. Almost two-thirds of the publications returned in the top-5 are relevant for clinical decision-support. Our approach enabled identifying 81.8% of clinically actionable variants in the top-3. Variomes retrieves on average +21.3% more articles than LitVar and returns the same number of results or more results than LitVar for 90% of the queries when tested on a set of 803 queries; thus, establishing a new baseline for searching the literature about variants. AVAILABILITY AND IMPLEMENTATION: Variomes is publicly available at https://candy.hesge.ch/Variomes. Source code is freely available at https://github.com/variomes/sibtm-variomes. SynVar is publicly available at https://goldorak.hesge.ch/synvar. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Feasibility of Reconstructing Source Functional Connectivity with Low-Density EEG.

OBJECTIVES: Functional connectivity (FC) is increasingly used as target for neuromodulation and enhancement of performance. A reliable assessment of FC with electroencephalography (EEG) currently requires a laboratory environment with high-density montages and a long preparation time. This study investigated the feasibility of reconstructing source FC with a low-density EEG montage towards a usage in real life applications. METHODS: Source FC was reconstructed with inverse solutions and quantified as node degree of absolute imaginary coherence in alpha frequencies. We used simulated coherent point sources as well as two real datasets to investigate the impact of electrode density (19 vs. 128 electrodes) and usage of template vs. individual MRI-based head models on localization accuracy. In addition, we checked whether low-density EEG is able to capture inter-individual variations in coherence strength. RESULTS: In numerical simulations as well as real data, a reduction of the number of electrodes led to less reliable reconstructions of coherent sources and of coupling strength. Yet, when comparing different approaches to reconstructing FC from 19 electrodes, source FC obtained with beamformers outperformed sensor FC, FC computed after independent component analysis, and source FC obtained with sLORETA. In particular, only source FC based on beamformers was able to capture neural correlates of motor behavior. CONCLUSION: Reconstructions of FC from low-density EEG is challenging, but may be feasible when using source reconstructions with beamformers.

Disrupted resting-state EEG alpha-band interactions as a novel marker for the severity of visual field deficits after brain lesion.

OBJECTIVE: Homonymous visual field deficits (HFVDs) are frequent following brain lesions. Current restoration treatments aim at activating areas of residual vision through numerous stimuli, but show limited effect. Recent findings suggest that spontaneous neural α-band coupling is more efficient for enabling visual perception in healthy humans than task-induced activations. Here, we evaluated whether it is also associated with the severity of HFVD. METHODS: Ten patients with HFVDs after brain damage in the subacute to chronic stage and ten matched healthy controls underwent visual stimulation with alternating checkerboards and electroencephalography recordings of stimulation-induced power changes and of spontaneous neural interactions during rest. RESULTS: Visual areas of the affected hemisphere showed reduced event-related power decrease in α and ß frequency bands, but also reduced spontaneous α-band interactions during rest, as compared to contralesional areas and healthy controls. A multivariate stepwise regression retained the degree of disruption of spontaneous interactions, but not the reduced task-induced power changes as predictor for the severity of the visual deficit. CONCLUSIONS: Spontaneous α-band interactions of visual areas appear as a better marker for the severity of HFVDs than task-induced activations. SIGNIFICANCE: Treatment attempts of HFVDs should try to enhance spontaneous α-band coupling of structurally intact ipsilesional areas.

Spontaneous Network Coupling Enables Efficient Task Performance without Local Task-Induced Activations.

Neurobehavioral studies in humans have long concentrated on changes in local activity levels during repetitive executions of a task. Spontaneous neural coupling within extended networks has latterly been found to also influence performance. Here, we intend to uncover the underlying mechanisms, the relative importance, and the interaction between spontaneous coupling and task-induced activations. To do so, we recorded two groups of healthy participants (male and female) during rest and while they performed either a visual perception or a motor sequence task. We demonstrate that, for both tasks, stronger activations during the task as well as greater network coupling through spontaneous α rhythms at rest predict performance. However, high performers present an absence of classical task-induced activations and, instead, stronger spontaneous network coupling. Activations were thus a compensation mechanism needed only in subjects with lower spontaneous network interactions. This challenges classical models of neural processing and calls for new strategies in attempts to train and enhance performance.SIGNIFICANCE STATEMENT Our findings challenge the widely accepted notion that task-induced activations are of paramount importance for behavior. This will have an important impact on interpretations of human neurobehavioral research. They further link the widely used techniques of quantifying network communication in the brain with classical neuroscience methods and demonstrate possible ways of how network communication influences human behavior. Traditional training methods attempt to enhance neural activations through task repetitions. Our findings suggest a more efficient neural target for learning: enhancing spontaneous neural interactions. This will be of major interest for a large variety of scientific fields with very broad applications in schools, work, and others.

The "implicit" serial reaction time task induces rapid and temporary adaptation rather than implicit motor learning.

The serial reaction time task (SRTT) has been widely used to induce learning of a repeated motor sequence without the participants' awareness. The task has also been of major influence for defining current concepts of offline consolidation after motor learning. The present study intended to replicate previous findings in a larger population of 53 healthy individuals. We were unable to reproduce previous results of online and offline implicit motor learning with the SRTT. Trials with a repeated sequence rapidly induced shorter reaction times compared to random trials, but this improvement was lost in a post-test obtained a few minutes after the training block. Furthermore, no offline consolidation was observed as there was no change in sequence specific reaction time gain between the post-test immediately after training and a re-test obtained 8 h after training. Online or offline learning remained absent when we modulated the number of sequence repetitions, the error levels, and the structure of random sequences. We conclude that the SRTT induces a rapid and temporary adaptation to the sequence rather than learning, since the repeated motor sequence does not seem to be encoded in memory.

Text-Mining Services of the Swiss Variant Interpretation Platform for Oncology.

The Swiss Variant Interpretation Platform for Oncology is a centralized, joint and curated database for clinical somatic variants piloted by a board of Swiss healthcare institutions and operated by the SIB Swiss Institute of Bioinformatics. To support this effort, SIB Text Mining designed a set of text analytics services. This report focuses on three of those services. First, the automatic annotations of the literature with a set of terminologies have been performed, resulting in a large annotated version of MEDLINE and PMC. Second, a generator of variant synonyms for single nucleotide variants has been developed using publicly available data resources, as well as patterns of non-standard formats, often found in the literature. Third, a literature ranking service enables to retrieve a ranked set of MEDLINE abstracts given a variant and optionally a diagnosis. The annotation of MEDLINE and PMC resulted in a total of respectively 785,181,199 and 1,156,060,212 annotations, which means an average of 26 and 425 annotations per abstract and full-text article. The generator of variant synonyms enables to retrieve up to 42 synonyms for a variant. The literature ranking service reaches a precision (P10) of 63%, which means that almost two-thirds of the top-10 returned abstracts are judged relevant. Further services will be implemented to complete this set of services, such as a service to retrieve relevant clinical trials for a patient and a literature ranking service for full-text articles.

Modulating functional connectivity after stroke with neurofeedback: Effect on motor deficits in a controlled cross-over study.

Synchronization of neural activity as measured with functional connectivity (FC) is increasingly used to study the neural basis of brain disease and to develop new treatment targets. However, solid evidence for a causal role of FC in disease and therapy is lacking. Here, we manipulated FC of the ipsilesional primary motor cortex in ten chronic human stroke patients through brain-computer interface technology with visual neurofeedback. We conducted a double-blind controlled crossover study to test whether manipulation of FC through neurofeedback had a behavioral effect on motor performance. Patients succeeded in increasing FC in the motor cortex. This led to improvement in motor function that was significantly greater than during neurofeedback training of a control brain area and proportional to the degree of FC enhancement. This result provides evidence that FC has a causal role in neurological function and that it can be effectively targeted with therapy.

Comparison of Neuroplastic Responses to Cathodal Transcranial Direct Current Stimulation and Continuous Theta Burst Stimulation in Subacute Stroke.

OBJECTIVE: To investigate the effects of cathodal transcranial direct current stimulation (tDCS) and continuous theta burst stimulation (cTBS) on neural network connectivity and motor recovery in individuals with subacute stroke. DESIGN: Double-blinded, randomized, placebo-controlled study. SETTING: University hospital rehabilitation unit. PARTICIPANTS: Inpatients with stroke (N=41; mean age, 65y; range, 28-85y; mean weeks poststroke, 5; range, 2-10) with resultant paresis in the upper extremity (mean Fugl-Meyer score, 14; range, 3-48). INTERVENTIONS: Subjects with stroke were randomly assigned to neuronavigated cTBS (n=14), cathodal tDCS (n=14), or sham transcranial magnetic stimulation/sham tDCS (n=13) over the contralesional primary motor cortex (M1). Each subject completed 9 stimulation sessions over 3 weeks, combined with physical therapy. MAIN OUTCOME MEASURES: Brain function was assessed with directed and nondirected functional connectivity based on high-density electroencephalography before and after stimulation sessions. Primary clinical end point was the change in slope of the multifaceted motor score composed of the upper extremity Fugl-Meyer Assessment score, Box and Block test score, 9-Hole Peg Test score, and Jamar dynamometer results between the baseline period and the treatment time. RESULTS: Neither stimulation treatment enhanced clinical motor gains. Cathodal tDCS and cTBS induced different neural effects. Only cTBS was able to reduce transcallosal influences from the contralesional to the ipsilesional M1 during rest. Conversely, tDCS enhanced perilesional beta-band oscillation coherence compared with cTBS and sham groups. Correlation analyses indicated that the modulation of interhemispheric driving and perilesional beta-band connectivity were not independent mediators for functional recovery across all patients. However, exploratory subgroup analyses suggest that the enhancement of perilesional beta-band connectivity through tDCS might have more robust clinical gains if started within the first 4 weeks after stroke. CONCLUSIONS: The inhibition of the contralesional M1 or the reduction of interhemispheric interactions was not clinically useful in the heterogeneous group of subjects with subacute stroke. An early modulation of perilesional oscillation coherence seems to be a more promising strategy for brain stimulation interventions.

Theta-band functional connectivity in the dorsal fronto-parietal network predicts goal-directed attention.

Functional imaging studies have identified a dorsal fronto-parietal network whose activity reflects shifts of attention in space and is sensitive to the behavioural relevance of stimuli. In patients with severe deficits of spatial attention this network is often structurally preserved. Here, we show that resting-state EEG functional connectivity in the dorsal fronto-parietal network predicts impaired goal-directed processing in stroke patients with spatial attention deficits. Eleven right-hemisphere damaged patients with different degrees of contralesional spatial deficits and sixteen age-matched healthy controls performed a visuo-spatial task which required them to react to a central target while ignoring task-relevant distracters presented left or right of fixation. Unlike controls, performance of patients was not modulated by the goal-relevance of peripheral distracters. Compared to controls patients showed a significant decrease in theta-band connectivity between the right dorsolateral prefrontal cortex and the right superior parietal region. Moreover, in both groups we observed a significant correlation between fronto-parietal connectivity and the behavioural effect of distracter relevance. These findings indicate that fronto-parietal functional connectivity is impaired in patients with spatial attention deficits and predicts effects of goal-relevant information on target processing.

Binaural beats increase interhemispheric alpha-band coherence between auditory cortices.

Binaural beats (BBs) are an auditory illusion occurring when two tones of slightly different frequency are presented separately to each ear. BBs have been suggested to alter physiological and cognitive processes through synchronization of the brain hemispheres. To test this, we recorded electroencephalograms (EEG) at rest and while participants listened to BBs or a monaural control condition during which both tones were presented to both ears. We calculated for each condition the interhemispheric coherence, which expressed the synchrony between neural oscillations of both hemispheres. Compared to monaural beats and resting state, BBs enhanced interhemispheric coherence between the auditory cortices. Beat frequencies in the alpha (10 Hz) and theta (4 Hz) frequency range both increased interhemispheric coherence selectively at alpha frequencies. In a second experiment, we evaluated whether this coherence increase has a behavioral aftereffect on binaural listening. No effects were observed in a dichotic digit task performed immediately after BBs presentation. Our results suggest that BBs enhance alpha-band oscillation synchrony between the auditory cortices during auditory stimulation. This effect seems to reflect binaural integration rather than entrainment.

Neurofeedback training of alpha-band coherence enhances motor performance.

OBJECTIVE: Neurofeedback training of motor cortex activations with brain-computer interface systems can enhance recovery in stroke patients. Here we propose a new approach which trains resting-state functional connectivity associated with motor performance instead of activations related to movements. METHODS: Ten healthy subjects and one stroke patient trained alpha-band coherence between their hand motor area and the rest of the brain using neurofeedback with source functional connectivity analysis and visual feedback. RESULTS: Seven out of ten healthy subjects were able to increase alpha-band coherence between the hand motor cortex and the rest of the brain in a single session. The patient with chronic stroke learned to enhance alpha-band coherence of his affected primary motor cortex in 7 neurofeedback sessions applied over one month. Coherence increased specifically in the targeted motor cortex and in alpha frequencies. This increase was associated with clinically meaningful and lasting improvement of motor function after stroke. CONCLUSIONS: These results provide proof of concept that neurofeedback training of alpha-band coherence is feasible and behaviorally useful. SIGNIFICANCE: The study presents evidence for a role of alpha-band coherence in motor learning and may lead to new strategies for rehabilitation.

Timing and awareness of movement decisions: does consciousness really come too late?

Since Libet's seminal observation that a brain potential related to movement preparation occurs before participants report to be aware of their movement intention, it has been debated whether consciousness has causal influence on movement decisions. Here we review recent advances that provide new insights into the dynamics of human decision-making and question the validity of different markers used for determining the onset of neural and conscious events. Motor decisions involve multiple stages of goal evaluation, intention formation, and action execution. While the validity of the Bereitschaftspotential (BP) as index of neural movement preparation is controversial, improved neural markers are able to predict decision outcome even at early stages. Participants report being conscious of their decisions only at the time of final intention formation, just before the primary motor cortex starts executing the chosen action. However, accumulating evidence suggests that this is an artifact of Libet's clock method used for assessing consciousness. More refined methods suggest that intention consciousness does not appear instantaneously but builds up progressively. In this view, early neural markers of decision outcome are not unconscious but simply reflect conscious goal evaluation stages which are not final yet and therefore not reported with the clock method. Alternatives to the Libet clock are discussed that might allow for assessment of consciousness during decision making with improved sensitivity to early decision stages and with less influence from meta-conscious and perceptual inferences.

Easy retrieval of single amino-acid polymorphisms and phenotype information using SwissVar.

SUMMARY: The SwissVar portal provides access to a comprehensive collection of single amino acid polymorphisms and diseases in the UniProtKB/Swiss-Prot database via a unique search engine. In particular, it gives direct access to the newly improved Swiss-Prot variant pages. The key strength of this portal is that it provides a possibility to query for similar diseases, as well as the underlying protein products and the molecular details of each variant. In the context of the recently proposed molecular view on diseases, the SwissVar portal should be in a unique position to provide valuable information for researchers and to advance research in this area. AVAILABILITY: The SwissVar portal is available at www.expasy.org/swissvar CONTACT: anais.mottaz@isb-sib.ch; lina.yip@isb-sib.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene Ontology density estimation and discourse analysis for automatic GeneRiF extraction.

BACKGROUND: This paper describes and evaluates a sentence selection engine that extracts a GeneRiF (Gene Reference into Functions) as defined in ENTREZ-Gene based on a MEDLINE record. Inputs for this task include both a gene and a pointer to a MEDLINE reference. In the suggested approach we merge two independent sentence extraction strategies. The first proposed strategy (LASt) uses argumentative features, inspired by discourse-analysis models. The second extraction scheme (GOEx) uses an automatic text categorizer to estimate the density of Gene Ontology categories in every sentence; thus providing a full ranking of all possible candidate GeneRiFs. A combination of the two approaches is proposed, which also aims at reducing the size of the selected segment by filtering out non-content bearing rhetorical phrases. RESULTS: Based on the TREC-2003 Genomics collection for GeneRiF identification, the LASt extraction strategy is already competitive (52.78%). When used in a combined approach, the extraction task clearly shows improvement, achieving a Dice score of over 57% (+10%). CONCLUSIONS: Argumentative representation levels and conceptual density estimation using Gene Ontology contents appear complementary for functional annotation in proteomics.

Mapping proteins to disease terminologies: from UniProt to MeSH.

BACKGROUND: Although the UniProt KnowledgeBase is not a medical-oriented database, it contains information on more than 2,000 human proteins involved in pathologies. However, these annotations are not standardized, which impairs the interoperability between biological and clinical resources. In order to make these data easily accessible to clinical researchers, we have developed a procedure to link diseases described in the UniProtKB/Swiss-Prot entries to the MeSH disease terminology. RESULTS: We mapped disease names extracted either from the UniProtKB/Swiss-Prot entry comment lines or from the corresponding OMIM entry to the MeSH. Different methods were assessed on a benchmark set of 200 disease names manually mapped to MeSH terms. The performance of the retained procedure in term of precision and recall was 86% and 64% respectively. Using the same procedure, more than 3,000 disease names in Swiss-Prot were mapped to MeSH with comparable efficiency. CONCLUSIONS: This study is a first attempt to link proteins in UniProtKB to the medical resources. The indexing we provided will help clinicians and researchers navigate from diseases to genes and from genes to diseases in an efficient way. The mapping is available at: http://research.isb-sib.ch/unimed.