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Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases.

ABSTRACT: Although standards and guidelines for the interpretation of variants identified in genes that cause Mendelian disorders have been developed, this is not the case for more complex genetic models including variant combinations in multiple genes. During a large curation process conducted on 318 research articles presenting oligogenic variant combinations, we encountered several recurring issues concerning their proper reporting and pathogenicity assessment. These mainly concern the absence of strong evidence that refutes a monogenic model and the lack of a proper genetic and functional assessment of the joint effect of the involved variants. With the increasing accumulation of such cases, it has become essential to develop standards and guidelines on how these oligogenic/multilocus variant combinations should be interpreted, validated, and reported in order to provide high-quality data and supporting evidence to the scientific community.

SUBMITTER: Papadimitriou S

PROVIDER: S-EPMC9791921 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases.

Papadimitriou Sofia S Gravel Barbara B Nachtegael Charlotte C De Baere Elfride E Loeys Bart B Vikkula Miikka M Smits Guillaume G Lenaerts Tom T

HGG advances 20221202 1

Although standards and guidelines for the interpretation of variants identified in genes that cause Mendelian disorders have been developed, this is not the case for more complex genetic models including variant combinations in multiple genes. During a large curation process conducted on 318 research articles presenting oligogenic variant combinations, we encountered several recurring issues concerning their proper reporting and pathogenicity assessment. These mainly concern the absence of stron ...[more]

PMID: 36578772

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Project description:While biomedical relation extraction (bioRE) datasets have been instrumental in the development of methods to support biocuration of single variants from texts, no datasets are currently available for the extraction of digenic or even oligogenic variant relations, despite the reports in literature that epistatic effects between combinations of variants in different loci (or genes) are important to understand disease etiologies. This work presents the creation of a unique dataset of oligogenic variant combinations, geared to train tools to help in the curation of scientific literature. To overcome the hurdles associated with the number of unlabelled instances and the cost of expertise, active learning (AL) was used to optimize the annotation, thus getting assistance in finding the most informative subset of samples to label. By pre-annotating 85 full-text articles containing the relevant relations from the Oligogenic Diseases Database (OLIDA) with PubTator, text fragments featuring potential digenic variant combinations, i.e. gene-variant-gene-variant, were extracted. The resulting fragments of texts were annotated with ALAMBIC, an AL-based annotation platform. The resulting dataset, called DUVEL, is used to fine-tune four state-of-the-art biomedical language models: BiomedBERT, BiomedBERT-large, BioLinkBERT and BioM-BERT. More than 500 000 text fragments were considered for annotation, finally resulting in a dataset with 8442 fragments, 794 of them being positive instances, covering 95% of the original annotated articles. When applied to gene-variant pair detection, BiomedBERT-large achieves the highest F1 score (0.84) after fine-tuning, demonstrating significant improvement compared to the non-fine-tuned model, underlining the relevance of the DUVEL dataset. This study shows how AL may play an important role in the creation of bioRE dataset relevant for biomedical curation applications. DUVEL provides a unique biomedical corpus focusing on 4-ary relations between two genes and two variants. It is made freely available for research on GitHub and Hugging Face. Database URL: https://huggingface.co/datasets/cnachteg/duvel or https://doi.org/10.57967/hf/1571.

Project description:BackgroundThe Guidelines International Network (G-I-N) aims to promote high quality clinical guideline development and implementation. Guideline-based performance measures are a key implementation tool and are widely used internationally for quality improvement, quality assurance, and pay for performance in health care. There is, however, no international consensus on best methods for guideline-based performance measures. In order to address this issue, the G-I-N Performance Measures Working Group aimed to develop a set of consensus-based reporting standards for guideline-based performance measure development and re-evaluation.MethodsMethodology publications on guideline-based performance measures were identified from a systematic literature review and analyzed. Core criteria for the development and evaluation process of guideline-based performance measures were determined and refined into draft standards with an associated rationale and description of the evidence base. In a two-round Delphi-process, the group members appraised and approved the draft standards. After the first round, the group met to discuss comments and revised the drafts accordingly.ResultsTwenty-one methodology publications were reviewed. The group reached strong consensus on nine reporting standards concerning: (1) selection of clinical guidelines, (2) extraction of clinical guideline recommendations, (3) description of the measure development process, (4) measure appraisal, (5) measure specification, (6) description of the intended use of the measure, (7) measure testing/validating, (8) measure review/re-evaluation, and (9) composition of the measure development panel.ConclusionsThese proposed international reporting standards address core components of guideline-based performance measure development and re-evaluation. They are intended to contribute to international reporting harmonization and improvement of methods for performance measures. Further research is required regarding validity, acceptability, and practicality.

Dataset Information

Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases.

Publications

Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases.

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