{"doi":"10.3390/genes15121522","title":"Genomic Landscape of Chromosome X Factor VIII: From Hemophilia A in Males to Risk Variants in Females","abstract":"BACKGROUND: Variants within factor VIII (F8) are associated with sex-linked hemophilia A and thrombosis, with gene therapy approaches being available for pathogenic variants. Many variants within F8 remain variants of uncertain significance (VUS) or are under-explored as to their connections to phenotypic outcomes. METHODS: We assessed data on F8 expression while screening the UniProt, ClinVar, Geno2MP, and gnomAD databases for F8 missense variants; these collectively represent the sequencing of more than a million individuals. RESULTS: For the two F8 isoforms coding for different protein lengths (2351 and 216 amino acids), we observed noncoding variants influencing expression which are also associated with thrombosis risk, with uncertainty as to differences in females and males. Variant analysis identified a severe stratification of potential annotation issues for missense variants in subjects of non-European ancestry, suggesting a need for further defining the genetics of diverse populations. Additionally, few heterozygous female carriers of known pathogenic variants have sufficiently confident phenotyping data, leaving researchers unable to determine subtle, less defined phenotypes. Using structure movement correlations to known pathogenic variants for the VUS, we determined seven clusters of likely pathogenic variants based on screening work. CONCLUSIONS: This work highlights the need to define missense variants, especially those for VUS and from subjects of non-European ancestry, as well as the roles of these variants in women's physiology.","journal":"Genes","year":2024,"id":482403,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":22.178386323199504,"corpus_rank":9377,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.5525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":62.5,"fair_percentile":81.0149801284011,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":426802,"name":"Michèle Morris","orcid":"0000-0003-2529-4597","position":1,"is_corresponding":false},{"id":810164,"name":"Shawn M. Jobe","orcid":"0000-0001-7878-6101","position":2,"is_corresponding":false},{"id":716030,"name":"Disha Bhargava","orcid":null,"position":3,"is_corresponding":false},{"id":1224896,"name":"Jena M. Krueger","orcid":"0009-0009-3471-3395","position":4,"is_corresponding":false},{"id":1322969,"name":"Sanjana Arora","orcid":null,"position":5,"is_corresponding":false},{"id":394893,"name":"Jeremy W. Prokop","orcid":"0000-0002-1818-9695","position":6,"is_corresponding":false},{"id":426801,"name":"Cynthia L. Stenger","orcid":"0000-0001-7014-4243","position":7,"is_corresponding":false},{"id":1322604,"name":"Olivia Morris","orcid":"0000-0002-9491-8060","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T02:07:14.349221Z","pmid":"39766791","pmcid":"PMC11675246","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":94.4444,"fair_a":62.5,"fair_i":0.0,"fair_r":25.0,"fair_zscore":1.1103,"fair_rationale":{"fair_score":62.5,"has_llm":true,"taxonomy_version":"fair_taxonomy_v5","dimensions":{"F":{"name":"Findable","score":94.44,"criteria":[{"key":"f_dataset_pid","label":"Persistent identifier for the data","kind":"llm","weight":2.0,"fraction":1.0,"verdict":"yes","evidence":"https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The paper provides a DOI for the dataset, which is a persistent identifier. [majority verdict 'yes' (4/5 passes agreed)]","anchors":["RDA-F1-01D — FAIR Data Maturity Model: 'Data is identified by a persistent identifier' (priorit","RDA-F1-02D — FAIR Data Maturity Model: 'Data is identified by a globally unique identifier'","FsF-F1-02D — F-UJI/FAIRsFAIR: 'Data is assigned a persistent identifier'"],"scored":true,"signal":null},{"key":"f_repository_named","label":"Named repository","kind":"llm","weight":2.0,"fraction":1.0,"verdict":"yes","evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The repository figshare is named as the holder of the data. [majority verdict 'yes' (4/5 passes agreed)]","anchors":["RDA-F4-01M — FAIR Data Maturity Model: metadata is offered so it can be harvested and indexed (","NIH DMS Policy Element 4 (NOT-OD-21-014) — name the repository where data will be archived","NSTC Desirable Characteristics of Data Repositories (2022) — 'Long-Term Sustainability', 'Reten"],"scored":true,"signal":null},{"key":"f_data_availability_statement","label":"Data-availability statement","kind":"llm","weight":2.0,"fraction":1.0,"verdict":"yes","evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The statement points to a repository record with a DOI (Colavizza category 3). [majority verdict 'yes' (4/5 passes agreed)]","anchors":["Colavizza, Hrynaszkiewicz, Staden, Whitaker & McGillivray (2020), 'The citation advantage of li","Springer Nature research data policy — Data Availability Statements: standard statement templat","RDA-F3-01M — metadata clearly and explicitly includes the identifier of the data it describes"],"scored":false,"signal":null},{"key":"f_discovery_metadata","label":"Description of the dataset as an object","kind":"llm","weight":2.0,"fraction":1.0,"verdict":"yes","evidence":"Amino Acids—The combined insight of conservation, UniProt annotations, and number of variants in various databases; Evolution_322_species—Sequence alignments from NCBI orthologs of F8; Variant table—All variants from following tabs;","grounded":true,"rationale":"The paper includes an itemised inventory of files in the Supplementary Materials section, serving as a structural description of the dataset. [majority verdict 'yes' (4/5 passes agreed)]","anchors":["RDA-F2-01M — 'Rich metadata is provided to allow discovery' (priority Essential)","FsF-F2-01M — F-UJI: 'Metadata includes descriptive core elements to support data findability'","FsF-R1-01MD — F-UJI: 'Metadata specifies the content of the data'"],"scored":false,"signal":null},{"key":"f_dataset_cited","label":"Dataset formally cited","kind":"llm","weight":1.0,"fraction":0.5,"verdict":"partial","evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The dataset identifier appears only in the body text (Data Availability Statement), not in the reference list. [majority verdict 'partial' (4/5 passes agreed)]","anchors":["FORCE11 Joint Declaration of Data Citation Principles (2014) — data should be cited as a first-","RDA-F3-01M — metadata clearly and explicitly includes the identifier of the data it describes","FsF-F3-01M — F-UJI: 'Metadata includes the identifier of the data it describes'"],"scored":true,"signal":null}]},"A":{"name":"Accessible","score":62.5,"criteria":[{"key":"a_data_openly_accessible","label":"Access route free of preconditions","kind":"llm","weight":2.0,"fraction":1.0,"verdict":"yes","evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The text gives a route to the data with no stated precondition — the data are openly available at figshare. [majority verdict 'yes' (4/5 passes agreed)]","anchors":["RDA-A1.1-01D — 'Data is accessible through a free access protocol'","FsF-A1-01M — F-UJI: 'Metadata contains access level and access conditions of the data'","NSTC Desirable Characteristics of Data Repositories (2022) — 'Free and Easy Access'"],"scored":true,"signal":null},{"key":"a_access_conditions_stated","label":"Access level labelled","kind":"llm","weight":1.0,"fraction":0.5,"verdict":"partial","evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The paper describes an access action (the URL) but does not apply an explicit access-level label such as 'open access' or 'freely available'. [majority verdict 'partial' (3/5 passes agreed)]","anchors":["FsF-A1-01M — F-UJI: 'Metadata contains access level and access conditions of the data'","RDA-A1-01M — metadata contains information to enable the user to get access to the data","COAR Controlled Vocabularies — Access Rights v1.0 (open / embargoed / restricted / metadata-onl"],"scored":false,"signal":null},{"key":"a_controlled_access_for_sensitive","label":"Gatekeeper for sensitive data","kind":"llm","weight":0.5,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"The paper's data are not sensitive human-subject data; no gatekeeper is named.","anchors":["NIH Genomic Data Sharing Policy (NOT-OD-14-124) — controlled-access via a Data Access Committee","RDA-A1.2-01D — 'Data is accessible through an access protocol that supports authentication and ","NIH DMS Policy Element 5 (NOT-OD-21-014) — Access, Distribution, or Reuse Considerations (conse"],"scored":false,"signal":null},{"key":"a_timeline_retention","label":"Availability timing & retention","kind":"llm","weight":0.5,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"The paper does not mention any retention period or availability timing for the data. [majority verdict 'no' (4/5 passes agreed)]","anchors":["NIH DMS Plan Element 4 (NOT-OD-21-014) — Data Preservation, Access, and Associated Timelines","NSTC Desirable Characteristics (2022), Organizational Infrastructure: 'Retention Policy'","RDA-A2-01M — 'Metadata is guaranteed to remain available after data is no longer available'"],"scored":false,"signal":null}]},"I":{"name":"Interoperable","score":0.0,"criteria":[{"key":"i_open_nonproprietary_format","label":"Open file format","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"The paper does not name any file format for the released data.","anchors":["FsF-R1.3-02D — F-UJI: 'Data is available in a file format recommended by the target research co","RDA-R1.3-02D — data is expressed in a machine-understandable community standard","RDA-I1-01D — data uses a knowledge representation expressed in a standardised format"],"scored":true,"signal":null},{"key":"i_community_standard_vocabulary","label":"Community standard / vocabulary","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No data or metadata community standard (e.g., MIAME, BIDS) is named for the released data. [majority verdict 'no' (4/5 passes agreed)]","anchors":["RDA-R1.3-01M — 'Metadata complies with a community standard' (priority Essential)","RDA-R1.3-01D — 'Data complies with a community standard'","RDA-I2-01M — '(Meta)data use vocabularies that follow FAIR principles'"],"scored":false,"signal":null},{"key":"i_qualified_references","label":"Identifiers for the resources the data depend on","kind":"llm","weight":0.5,"fraction":0.0,"verdict":"no","evidence":"Bulk tissue expression was annotated from the GTEx version 8","grounded":false,"rationale":"The paper provides an identifier (version 8) for the GTEx resource, which is not the paper's own dataset. [downgraded to 'no' — no verifiable quote from the paper] [majority verdict 'no' (4/5 passes agreed)]","anchors":["RDA-I3-01M — '(meta)data include references to other (meta)data'","RDA-I3-03M — 'metadata includes qualified references to other metadata'","FsF-I3-01M — F-UJI: 'Metadata includes links between the data and its related entities'"],"scored":false,"signal":null}]},"R":{"name":"Reusable","score":25.0,"criteria":[{"key":"r_reuse_license","label":"Reuse licence","kind":"llm","weight":2.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No license or reuse terms are stated for the data.","anchors":["RDA-R1.1-01M — 'Metadata includes information about the licence under which the data can be reu","RDA-R1.1-02M — 'Metadata refers to a standard reuse licence'","RDA-R1.1-03M — 'Metadata refers to a machine-understandable reuse licence'"],"scored":true,"signal":null},{"key":"r_provenance_methods","label":"Provenance of the data","kind":"llm","weight":1.0,"fraction":0.5,"verdict":"partial","evidence":"YASARA [48] modeling","grounded":false,"rationale":"The paper names specific software and instruments used to produce the data. [downgraded to 'partial' — no verifiable quote from the paper] [majority verdict 'partial' (3/5 passes agreed)]","anchors":["RDA-R1.2-01M — 'Metadata includes provenance information according to community- specific standa","FsF-R1.2-01M — F-UJI: 'Metadata includes provenance information about data creation or generati","W3C PROV-O (W3C Recommendation, 2013) — the entity/activity/agent model of provenance"],"scored":false,"signal":null},{"key":"r_documentation_codebook","label":"Documentation / codebook","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"No README, data dictionary, or codebook is named as accompanying the data; the paper itself contains variable definitions in tables. [majority verdict 'no' (3/5 passes agreed)]","anchors":["RDA-R1-01M — '(Meta)data are richly described with a plurality of accurate and relevant attribu","FsF-R1-01MD — F-UJI: 'Metadata specifies the content of the data'","NIH DMS Policy Element 3 (NOT-OD-21-014) — Standards (documentation and metadata to accompany t"],"scored":false,"signal":null},{"key":"r_versioning","label":"Snapshot identified","kind":"llm","weight":0.5,"fraction":1.0,"verdict":"yes","evidence":"https://doi.org/10.6084/m9.figshare.26499532.v1","grounded":true,"rationale":"The DOI includes a version token (v1), identifying the snapshot. [majority verdict 'yes' (3/5 passes agreed)]","anchors":["DataCite Metadata Schema 4.6 — the 'Version' property","RDA-R1.2-01M — provenance information (which version was used is provenance)","NSTC Desirable Characteristics of Data Repositories (2022) — 'Provenance', 'Retention Policy'"],"scored":true,"signal":null},{"key":"x_code_availability","label":"Analysis code available","kind":"llm","weight":1.0,"fraction":0.0,"verdict":"no","evidence":null,"grounded":false,"rationale":"The paper does not provide any locator for the study's own code.","anchors":["NIH DMS Policy Element 2 (NOT-OD-21-014) — 'Related Tools, Software and/or Code'","FAIR4RS Principles v1.0 (Chue Hong et al., 2022; RDA/FORCE11/ReSA) — FAIR Principles for Resear","FORCE11 Software Citation Principles (Smith, Katz & Niemeyer, 2016, PeerJ CS 2:e86)"],"scored":true,"signal":null},{"key":"x_funding_attribution","label":"Funder and award number","kind":"llm","weight":0.5,"fraction":1.0,"verdict":"yes","evidence":"R01AI171984","grounded":true,"rationale":"The paper includes an alphanumeric grant number (R01AI171984) attached to a named funder. [majority verdict 'yes' (4/5 passes agreed)]","anchors":["DataCite Metadata Schema 4.6 — 'FundingReference' property (funderName, funderIdentifier, award","Crossref Funder Registry — canonical funder identifiers for funding metadata","RDA-F2-01M — rich metadata provided to allow discovery (funding is part of the descriptive reco"],"scored":true,"signal":null}]}},"actions":[{"key":"r_reuse_license","dimension":"R","label":"Reuse licence","action":"Attach a standard, machine-readable open licence to the deposit — CC0 or CC BY, which is what Horizon Europe and most funders expect — and print the licence identifier in the paper. 'Free to use' is not a licence: it grants nothing a reuser's institution can rely on.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No license or reuse terms are stated for the data.","gain":16.67,"priority":"essential","scored":true},{"key":"i_open_nonproprietary_format","dimension":"I","label":"Open file format","action":"Release the data in an open, community-standard format (CSV/TSV, JSON, HDF5, NetCDF, FASTQ, VCF, NIfTI…) instead of — or alongside — any proprietary or instrument-native format, and name the format in the paper. A dataset that needs a €2,000 licence to open is not reusable. Prefer open genomics / sequencing formats such as FASTQ, BAM or VCF.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"The paper does not name any file format for the released data.","gain":8.33,"priority":"important","scored":true},{"key":"x_code_availability","dimension":"R","label":"Analysis code available","action":"Publish the analysis code in a public forge, archive a tagged release with a DOI (Zenodo/Software Heritage), and cite that DOI in the paper. NIH DMS Element 2 asks for the tools and code, not only the data — and 'available on request' is not a locator. Archive the analysis code in a versioned repository (GitHub + a Zenodo release DOI).","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"The paper does not provide any locator for the study's own code.","gain":8.33,"priority":"important","scored":true},{"key":"f_dataset_cited","dimension":"F","label":"Dataset formally cited","action":"Cite the dataset in the reference list like a publication — creator, year, title, repository, DOI/accession — and cite it in-text where it is used. Only a reference- list entry is machine-readable to Crossref/DataCite, and only a citation lets the data earn credit. Cite the genomics / sequencing repository accession (e.g. from GEO (GSE accession), SRA (SRP/SRR) or ENA/BioProject (PRJEB/PRJNA)) in the reference list.","anchors":["yes","partial","no"],"verdict":"partial","current":0.5,"evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","why":"The dataset identifier appears only in the body text (Data Availability Statement), not in the reference list. [majority verdict 'partial' (4/5 passes agreed)]","gain":4.17,"priority":"important","scored":true},{"key":"a_access_conditions_stated","dimension":"A","label":"Access level labelled","action":"State the access level in words, using the standard vocabulary: 'These data are open access' / 'These data are controlled access'. A reader — and a harvester — should not have to infer the access level from the presence of a download link.","anchors":["yes","partial","no"],"verdict":"partial","current":0.5,"evidence":"Raw organized data are available at https://doi.org/10.6084/m9.figshare.26499532.v1","why":"The paper describes an access action (the URL) but does not apply an explicit access-level label such as 'open access' or 'freely available'. [majority verdict 'partial' (3/5 passes agreed)]","gain":0.0,"priority":"important","scored":false},{"key":"i_community_standard_vocabulary","dimension":"I","label":"Community standard / vocabulary","action":"Adopt and NAME your domain's data standard — the minimum-information checklist, metadata schema, or ontology your community uses (MIAME/MINSEQE, ISA-Tab, BIDS, an OBO ontology, HL7 FHIR/OMOP) — and say which one you followed. A reporting checklist standardises your paper; it does nothing for your data. In genomics / sequencing, describe the data with MIAME, MINSEQE or MIxS.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No data or metadata community standard (e.g., MIAME, BIDS) is named for the released data. [majority verdict 'no' (4/5 passes agreed)]","gain":0.0,"priority":"important","scored":false},{"key":"r_provenance_methods","dimension":"R","label":"Provenance of the data","action":"Name the instruments, kits, and software — with versions — that produced the data, not just the verbs. 'Reads were aligned' is not provenance; 'aligned with STAR v2.7.9a to GRCh38' is, because someone else can rerun it.","anchors":["yes","partial","no"],"verdict":"partial","current":0.5,"evidence":"YASARA [48] modeling","why":"The paper names specific software and instruments used to produce the data. [downgraded to 'partial' — no verifiable quote from the paper] [majority verdict 'partial' (3/5 passes agreed)]","gain":0.0,"priority":"important","scored":false},{"key":"r_documentation_codebook","dimension":"R","label":"Documentation / codebook","action":"Ship a README and a data dictionary IN the deposit — every file, every variable, its units, its allowed values, its missing-value codes. It is the cheapest single thing that makes a dataset usable by someone who was not in the lab, and a table buried in the article does not travel with the data.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"No README, data dictionary, or codebook is named as accompanying the data; the paper itself contains variable definitions in tables. [majority verdict 'no' (3/5 passes agreed)]","gain":0.0,"priority":"important","scored":false},{"key":"a_controlled_access_for_sensitive","dimension":"A","label":"Gatekeeper for sensitive data","action":"Route sensitive data through an institutional gatekeeper — deposit in a controlled- access repository (dbGaP, EGA) with a Data Access Committee and a published DUA — rather than through the corresponding author's inbox. An author-gated dataset dies with the author's email address, and 'on reasonable request' has been shown repeatedly not to yield data. For sensitive/human genomics / sequencing data, use a controlled-access repository such as dbGaP or EGA.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"The paper's data are not sensitive human-subject data; no gatekeeper is named.","gain":0.0,"priority":"useful","scored":false},{"key":"i_qualified_references","dimension":"I","label":"Identifiers for the resources the data depend on","action":"Cite by identifier every resource the data depend on — the source datasets' accessions, the reference build (GRCh38 / GCA_000001405.28), the cohort application number, the code DOI — and register those relations on the dataset record (IsDerivedFrom, IsSupplementTo). A name is not a link: it cannot be resolved, versioned, or followed by a machine.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":"Bulk tissue expression was annotated from the GTEx version 8","why":"The paper provides an identifier (version 8) for the GTEx resource, which is not the paper's own dataset. [downgraded to 'no' — no verifiable quote from the paper] [majority verdict 'no' (4/5 passes agreed)]","gain":0.0,"priority":"useful","scored":false},{"key":"a_timeline_retention","dimension":"A","label":"Availability timing & retention","action":"State when the data become available AND how long they will be retained — cite the repository's preservation policy. NIH DMS Element 4 asks for both; most papers give neither.","anchors":["yes","partial","no"],"verdict":"no","current":0.0,"evidence":null,"why":"The paper does not mention any retention period or availability timing for the data. [majority verdict 'no' (4/5 passes agreed)]","gain":0.0,"priority":"useful","scored":false}],"suggestions":["Attach a standard, machine-readable open licence to the deposit — CC0 or CC BY, which is what Horizon Europe and most funders expect — and print the licence identifier in the paper. 'Free to use' is not a licence: it grants nothing a reuser's institution can rely on.","Release the data in an open, community-standard format (CSV/TSV, JSON, HDF5, NetCDF, FASTQ, VCF, NIfTI…) instead of — or alongside — any proprietary or instrument-native format, and name the format in the paper. A dataset that needs a €2,000 licence to open is not reusable. Prefer open genomics / sequencing formats such as FASTQ, BAM or VCF.","Publish the analysis code in a public forge, archive a tagged release with a DOI (Zenodo/Software Heritage), and cite that DOI in the paper. NIH DMS Element 2 asks for the tools and code, not only the data — and 'available on request' is not a locator. Archive the analysis code in a versioned repository (GitHub + a Zenodo release DOI).","Cite the dataset in the reference list like a publication — creator, year, title, repository, DOI/accession — and cite it in-text where it is used. Only a reference- list entry is machine-readable to Crossref/DataCite, and only a citation lets the data earn credit. Cite the genomics / sequencing repository accession (e.g. from GEO (GSE accession), SRA (SRP/SRR) or ENA/BioProject (PRJEB/PRJNA)) in the reference list.","State the access level in words, using the standard vocabulary: 'These data are open access' / 'These data are controlled access'. A reader — and a harvester — should not have to infer the access level from the presence of a download link."],"model":"deepseek/deepseek-v4-flash","agent_version":"fair_agent_v8","fulltext_source":"epmc_xml"},"fair_model":"deepseek/deepseek-v4-flash","fair_agent_version":"fair_agent_v8","fair_fulltext_source":"epmc_xml","fair_has_llm":true,"fair_computed_at":"2026-07-20T13:41:22.424503Z","clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}