CAGI SickKids challenges: Assessment of phenotype and variant predictions derived from clinical and genomic data of children with undiagnosed diseases.

Whole-genome sequencing (WGS) holds great potential as a diagnostic test. However, the majority of patients currently undergoing WGS lack a molecular diagnosis, largely due to the vast number of undiscovered disease genes and our inability to assess the pathogenicity of most genomic variants. The CAGI SickKids challenges attempted to address this knowledge gap by assessing state-of-the-art methods for clinical phenotype prediction from genomes. CAGI4 and CAGI5 participants were provided with WGS data and clinical descriptions of 25 and 24 undiagnosed patients from the SickKids Genome Clinic Project, respectively. Predictors were asked to identify primary and secondary causal variants. In addition, for CAGI5, groups had to match each genome to one of three disorder categories (neurologic, ophthalmologic, and connective), and separately to each patient. The performance of matching genomes to categories was no better than random but two groups performed significantly better than chance in matching genomes to patients. Two of the ten variants proposed by two groups in CAGI4 were deemed to be diagnostic, and several proposed pathogenic variants in CAGI5 are good candidates for phenotype expansion. We discuss implications for improving in silico assessment of genomic variants and identifying new disease genes.

Multi-label classification for biomedical literature: an overview of the BioCreative VII LitCovid Track for COVID-19 literature topic annotations.

The coronavirus disease 2019 (COVID-19) pandemic has been severely impacting global society since December 2019. The related findings such as vaccine and drug development have been reported in biomedical literature-at a rate of about 10 000 articles on COVID-19 per month. Such rapid growth significantly challenges manual curation and interpretation. For instance, LitCovid is a literature database of COVID-19-related articles in PubMed, which has accumulated more than 200 000 articles with millions of accesses each month by users worldwide. One primary curation task is to assign up to eight topics (e.g. Diagnosis and Treatment) to the articles in LitCovid. The annotated topics have been widely used for navigating the COVID literature, rapidly locating articles of interest and other downstream studies. However, annotating the topics has been the bottleneck of manual curation. Despite the continuing advances in biomedical text-mining methods, few have been dedicated to topic annotations in COVID-19 literature. To close the gap, we organized the BioCreative LitCovid track to call for a community effort to tackle automated topic annotation for COVID-19 literature. The BioCreative LitCovid dataset-consisting of over 30 000 articles with manually reviewed topics-was created for training and testing. It is one of the largest multi-label classification datasets in biomedical scientific literature. Nineteen teams worldwide participated and made 80 submissions in total. Most teams used hybrid systems based on transformers. The highest performing submissions achieved 0.8875, 0.9181 and 0.9394 for macro-F1-score, micro-F1-score and instance-based F1-score, respectively. Notably, these scores are substantially higher (e.g. 12%, higher for macro F1-score) than the corresponding scores of the state-of-art multi-label classification method. The level of participation and results demonstrate a successful track and help close the gap between dataset curation and method development. The dataset is publicly available via https://ftp.ncbi.nlm.nih.gov/pub/lu/LitCovid/biocreative/ for benchmarking and further development. Database URL https://ftp.ncbi.nlm.nih.gov/pub/lu/LitCovid/biocreative/.

Benchmarked approaches for reconstruction of in vitro cell lineages and in silico models of C. elegans and M. musculus developmental trees.

The recent advent of CRISPR and other molecular tools enabled the reconstruction of cell lineages based on induced DNA mutations and promises to solve the ones of more complex organisms. To date, no lineage reconstruction algorithms have been rigorously examined for their performance and robustness across dataset types and number of cells. To benchmark such methods, we decided to organize a DREAM challenge using in vitro experimental intMEMOIR recordings and in silico data for a C. elegans lineage tree of about 1,000 cells and a Mus musculus tree of 10,000 cells. Some of the 22 approaches submitted had excellent performance, but structural features of the trees prevented optimal reconstructions. Using smaller sub-trees as training sets proved to be a good approach for tuning algorithms to reconstruct larger trees. The simulation and reconstruction methods here generated delineate a potential way forward for solving larger cell lineage trees such as in mouse.

PRIORI-T: A tool for rare disease gene prioritization using MEDLINE.

INTRODUCTION: Phenotype-driven rare disease gene prioritization relies on high quality curated resources containing disease, gene and phenotype annotations. However, the effectiveness of gene prioritization tools is constrained by the incomplete coverage of rare disease, phenotype and gene annotations in such curated resources. METHODS: We extracted rare disease correlation pairs involving diseases, phenotypes and genes from MEDLINE abstracts and used the information propagation algorithm GCAS to build an association network. We built a tool called PRIORI-T for rare disease gene prioritization that uses this network for phenotype-driven rare disease gene prioritization. The quality of disease-gene associations in PRIORI-T was compared with resources such as DisGeNET and Open Targets in the context of rare diseases. The gene prioritization performance of PRIORI-T was evaluated using phenotype descriptions of 230 real-world rare disease clinical cases collated from recent publications, as well as compared to other gene prioritization tools such as HANRD and Orphamizer. RESULTS: PRIORI-T contains qualitatively better associations than DisGeNET and Open Targets. Furthermore, the causal genes were captured within Top-50 for more than 40% of the real-world clinical cases and within Top-300 for more than 72% of the cases when PRIORI-T was used for gene prioritization. It outperformed other gene prioritization tools such as HANRD and Orphamizer that primarily rely on curated resources. CONCLUSIONS: PRIORI-T exhibited improved gene prioritization performance without requiring high quality curated data. Thus, it holds great promise in phenotype-driven gene prioritization for rare disease studies.

Sequence Alignment on Directed Graphs.

Genomic variations in a reference collection are naturally represented as genome variation graphs. Such graphs encode common subsequences as vertices and the variations are captured using additional vertices and directed edges. The resulting graphs are directed graphs possibly with cycles. Existing algorithms for aligning sequences on such graphs make use of partial order alignment (POA) techniques that work on directed acyclic graphs (DAGs). To achieve this, acyclic extensions of the input graphs are first constructed through expensive loop unrolling steps (DAGification). Furthermore, such graph extensions could have considerable blowup in their size and in the worst case the blow-up factor is proportional to the input sequence length. We provide a novel alignment algorithm V-ALIGN that aligns the input sequence directly on the input graph while avoiding such expensive DAGification steps. V-ALIGN is based on a novel dynamic programming (DP) formulation that allows gapped alignment directly on the input graph. It supports affine and linear gaps. We also propose refinements to V-ALIGN for better performance in practice. With the proposed refinements, the time to fill the DP table has linear dependence on the sizes of the sequence, the graph, and its feedback vertex set. We conducted experiments to compare the proposed algorithm against the existing POA-based techniques. We also performed alignment experiments on the genome variation graphs constructed from the 1000 Genomes data. For aligning short sequences, standard approaches restrict the expensive gapped alignment to small filtered subgraphs having high similarity to the input sequence. In such cases, the performance of V-ALIGN for gapped alignment on the filtered subgraph depends on the subgraph sizes.

Phenotype-driven gene prioritization for rare diseases using graph convolution on heterogeneous networks.

BACKGROUND: One of the major goals of genomic medicine is the identification of causal genomic variants in a patient and their relation to the observed clinical phenotypes. Prioritizing the genomic variants by considering only the genotype information usually identifies a few hundred potential variants. Narrowing it down further to find the causal disease genes and relating them to the observed clinical phenotypes remains a significant challenge, especially for rare diseases. METHODS: We propose a phenotype-driven gene prioritization approach using heterogeneous networks in the context of rare diseases. Towards this, we first built a heterogeneous network consisting of ontological associations as well as curated associations involving genes, diseases, phenotypes and pathways from multiple sources. Motivated by the recent progress in spectral graph convolutions, we developed a graph convolution based technique to infer new phenotype-gene associations from this initial set of associations. We included these inferred associations in the initial network and termed this integrated network HANRD (Heterogeneous Association Network for Rare Diseases). We validated this approach on 230 recently published rare disease clinical cases using the case phenotypes as input. RESULTS: When HANRD was queried with the case phenotypes as input, the causal genes were captured within Top-50 for more than 31% of the cases and within Top-200 for more than 56% of the cases. The results showed improved performance when compared to other state-of-the-art tools. CONCLUSIONS: In this study, we showed that the heterogeneous network HANRD, consisting of curated, ontological and inferred associations, helped improve causal gene identification in rare diseases. HANRD allows future enhancements by supporting incorporation of new entity types and additional information sources.

TPX: Biomedical literature search made easy.

UNLABELLED: TPX is a web-based PubMed search enhancement tool that enables faster article searching using analysis and exploration features. These features include identification of relevant biomedical concepts from search results with linkouts to source databases, concept based article categorization, concept assisted search and filtering, query refinement. A distinguishing feature here is the ability to add user-defined concept names and/or concept types for named entity recognition. The tool allows contextual exploration of knowledge sources by providing concept association maps derived from the MEDLINE repository. It also has a full-text search mode that can be configured on request to access local text repositories, incorporating entity co-occurrence search at sentence/paragraph levels. Local text files can also be analyzed on-the-fly. AVAILABILITY: http://tpx.atc.tcs.com