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1.
medRxiv ; 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-39006426

RESUMEN

Objective: An increased risk of primary biliary cholangitis (PBC) has been reported in patients with systemic sclerosis (SSc). Our study aims to investigate the shared genetic susceptibility between the two disorders and to define candidate causal genes using cross-phenotype GWAS meta-analysis. Methods: We performed cross-phenotype GWAS meta-analysis and colocalization analysis for SSc and PBC. We performed both genome-wide and locus-based analysis, including tissue and pathway enrichment analyses, fine-mapping, colocalization analyses with expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets, and phenome-wide association studies (PheWAS). Finally, we used an integrative approach to prioritize candidate causal genes from the novel loci. Results: We detected a strong genetic correlation between SSc and PBC (rg = 0.84, p = 1.7 × 10-6). In the cross-phenotype GWAS meta-analysis, we identified 44 non-HLA loci that reached genome-wide significance (p < 5 × 10-8). Evidence of shared causal variants between SSc and PBC was found for nine loci, five of which were novel. Integrating multiple sources of evidence, we prioritized CD40, ERAP1, PLD4, SPPL3, and CCDC113 as novel candidate causal genes. The CD40 risk locus colocalized with trans-pQTLs of multiple plasma proteins involved in B cell function. Conclusion: Our study supports a strong shared genetic susceptibility between SSc and PBC. Through cross-phenotype analyses, we have prioritized several novel candidate causal genes and pathways for these disorders.

3.
Funct Integr Genomics ; 24(3): 104, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38764005

RESUMEN

Accurate estimation of population allele frequency (AF) is crucial for gene discovery and genetic diagnostics. However, determining AF for frameshift-inducing small insertions and deletions (indels) faces challenges due to discrepancies in mapping and variant calling methods. Here, we propose an innovative approach to assess indel AF. We developed CRAFTS-indels (Calculating Regional Allele Frequency Targeting Small indels), an algorithm that combines AF of distinct indels within a given region and provides "regional AF" (rAF). We tested and validated CRAFTS-indels using three independent datasets: gnomAD v2 (n=125,748 samples), an internal dataset (IGM; n=39,367), and the UK BioBank (UKBB; n=469,835). By comparing rAF against standard AF, we identified rare indels with rAF exceeding standard AF (sAF≤10-4 and rAF>10-4) as "rAF-hi" indels. Notably, a high percentage of rare indels were "rAF-hi", with a higher proportion in gnomAD v2 (11-20%) and IGM (11-22%) compared to the UKBB (5-9% depending on the CRAFTS-indels' parameters). Analysis of the overlap of regions based on their rAF with low complexity regions and with ClinVar classification supported the pertinence of rAF. Using the internal dataset, we illustrated the utility of CRAFTS-indel in the analysis of de novo variants and the potential negative impact of rAF-hi indels in gene discovery. In summary, annotation of indels with cohort specific rAF can be used to handle some of the limitations of current annotation pipelines and facilitate detection of novel gene disease associations. CRAFTS-indels offers a user-friendly approach to providing rAF annotation. It can be integrated into public databases such as gnomAD, UKBB and used by ClinVar to revise indel classifications.


Asunto(s)
Frecuencia de los Genes , Mutación INDEL , Humanos , Algoritmos
4.
Nat Commun ; 15(1): 3384, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38649760

RESUMEN

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.


Asunto(s)
Predisposición Genética a la Enfermedad , Leucopenia , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Humanos , Recuento de Leucocitos , Masculino , Femenino , Leucopenia/genética , Leucopenia/sangre , Persona de Mediana Edad , Anciano , Adulto , Inmunosupresores/uso terapéutico
5.
medRxiv ; 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38645167

RESUMEN

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGSBMI) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R2 being nearly double between best and worst performing quintiles for certain covariates. 28 covariates had significant PGSBMI-covariate interaction effects, modifying PGSBMI effects by nearly 20% per standard deviation change. We observed overlap between covariates that had significant R2 differences among strata and interaction effects - across all covariates, their main effects on BMI were correlated with their maximum R2 differences and interaction effects (0.56 and 0.58, respectively), suggesting high-PGSBMI individuals have highest R2 and increase in PGS effect. Using quantile regression, we show the effect of PGSBMI increases as BMI itself increases, and that these differences in effects are directly related to differences in R2 when stratifying by different covariates. Given significant and replicable evidence for context-specific PGSBMI performance and effects, we investigated ways to increase model performance taking into account non-linear effects. Machine learning models (neural networks) increased relative model R2 (mean 23%) across datasets. Finally, creating PGSBMI directly from GxAge GWAS effects increased relative R2 by 7.8%. These results demonstrate that certain covariates, especially those most associated with BMI, significantly affect both PGSBMI performance and effects across diverse cohorts and ancestries, and we provide avenues to improve model performance that consider these effects.

6.
Nat Genet ; 56(4): 605-614, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38514782

RESUMEN

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Encéfalo/metabolismo , Sitios de Carácter Cuantitativo/genética , Variación Genética/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética
7.
Nat Med ; 30(2): 480-487, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38374346

RESUMEN

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.


Asunto(s)
Enfermedad Crónica , Puntuación de Riesgo Genético , Salud Poblacional , Adulto , Niño , Humanos , Comunicación , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Estados Unidos
8.
Prenat Diagn ; 44(3): 343-351, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38285371

RESUMEN

OBJECTIVE: GREB1L has been linked prenatally to Potter's sequence, as well as less severe anomalies of the kidney, uterus, inner ear, and heart. The full phenotypic spectrum is unknown. The purpose of this study was to characterize known and novel pre- and postnatal phenotypes associated with GREB1L. METHODS: We solicited cases from the Fetal Sequencing Consortium, screened a population-based genomic database, and conducted a comprehensive literature search to identify disease cases associated with GREB1L. We present a detailed phenotypic spectrum and molecular changes. RESULTS: One hundred twenty-seven individuals with 51 unique pathogenic or likely pathogenic GREB1L variants were identified. 24 (47%) variants were associated with isolated kidney anomalies, 19 (37%) with anomalies of multiple systems, including one case of hypoplastic left heart syndrome, five (10%) with isolated sensorineural hearing loss, two (4%) with isolated uterine agenesis; and one (2%) with isolated tetralogy of Fallot. CONCLUSION: GREB1L may cause complex congenital heart disease (CHD) in humans. Clinicians should consider GREB1L testing in the setting of CHD, and cardiac screening in the setting of GREB1L variants.


Asunto(s)
Cardiopatías Congénitas , Enfermedades Renales , Anomalías Urogenitales , Femenino , Humanos , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/genética , Riñón/anomalías , Enfermedades Renales/congénito , Proteínas de Neoplasias/genética , Anomalías Urogenitales/genética
9.
J Am Med Inform Assoc ; 31(2): 306-316, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-37860921

RESUMEN

OBJECTIVE: Developing targeted, culturally competent educational materials is critical for participant understanding of engagement in a large genomic study that uses computational pipelines to produce genome-informed risk assessments. MATERIALS AND METHODS: Guided by the Smerecnik framework that theorizes understanding of multifactorial genetic disease through 3 knowledge types, we developed English and Spanish infographics for individuals enrolled in the Electronic Medical Records and Genomics Network. Infographics were developed to explain concepts in lay language and visualizations. We conducted iterative sessions using a modified "think-aloud" process with 10 participants (6 English, 4 Spanish-speaking) to explore comprehension of and attitudes towards the infographics. RESULTS: We found that all but one participant had "awareness knowledge" of genetic disease risk factors upon viewing the infographics. Many participants had difficulty with "how-to" knowledge of applying genetic risk factors to specific monogenic and polygenic risks. Participant attitudes towards the iteratively-refined infographics indicated that design saturation was reached. DISCUSSION: There were several elements that contributed to the participants' comprehension (or misunderstanding) of the infographics. Visualization and iconography techniques best resonated with those who could draw on prior experiences or knowledge and were absent in those without. Limited graphicacy interfered with the understanding of absolute and relative risks when presented in graph format. Notably, narrative and storytelling theory that informed the creation of a vignette infographic was most accessible to all participants. CONCLUSION: Engagement with the intended audience who can identify strengths and points for improvement of the intervention is necessary to the development of effective infographics.


Asunto(s)
Visualización de Datos , Registros Electrónicos de Salud , Humanos , Comunicación , Genómica , Educación en Salud/métodos
11.
Nat Commun ; 14(1): 8318, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38097619

RESUMEN

Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.


Asunto(s)
Riñón Poliquístico Autosómico Dominante , Insuficiencia Renal Crónica , Humanos , Penetrancia , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/complicaciones , Herencia Multifactorial/genética , Factores de Riesgo
12.
Nat Commun ; 14(1): 7836, 2023 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-38036523

RESUMEN

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.


Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Humanos , Glomeruloesclerosis Focal y Segmentaria/genética , Apolipoproteína L1/genética , Predisposición Genética a la Enfermedad , Factores de Riesgo , Genotipo , Apolipoproteínas/genética
13.
Genet Med ; 25(12): 100983, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37746849

RESUMEN

PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. RESULTS: Results demonstrate ∼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to ∼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.


Asunto(s)
Epilepsia , Sistema Urinario , Anomalías Urogenitales , Animales , Ratones , Humanos , Penetrancia , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Anomalías Urogenitales/genética , Riñón/anomalías , Factores de Riesgo , Epilepsia/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética
14.
medRxiv ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37662324

RESUMEN

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio=0.55 per standard deviation increase in PGSWBC [95%CI, 0.30 - 0.94], p=0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n=1,724, hazard ratio [HR]=0.78 [0.69 - 0.88], p=4.0×10-5) or immunosuppressant (n=354, HR=0.61 [0.38 - 0.99], p=0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n=1,466, HR=0.62 [0.44 - 0.87], p=0.006). Collectively, these findings suggest that a WBC count polygenic score identifies individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

15.
medRxiv ; 2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37577628

RESUMEN

Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

16.
medRxiv ; 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37503172

RESUMEN

Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

18.
medRxiv ; 2023 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-37333246

RESUMEN

Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.

19.
Nat Genet ; 55(7): 1091-1105, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37337107

RESUMEN

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.


Asunto(s)
Glomerulonefritis por IGA , Animales , Ratones , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/diagnóstico , Estudio de Asociación del Genoma Completo , Inmunoglobulina A/genética
20.
JAMIA Open ; 6(2): ooad032, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37181728

RESUMEN

With the burgeoning development of computational phenotypes, it is increasingly difficult to identify the right phenotype for the right tasks. This study uses a mixed-methods approach to develop and evaluate a novel metadata framework for retrieval of and reusing computational phenotypes. Twenty active phenotyping researchers from 2 large research networks, Electronic Medical Records and Genomics and Observational Health Data Sciences and Informatics, were recruited to suggest metadata elements. Once consensus was reached on 39 metadata elements, 47 new researchers were surveyed to evaluate the utility of the metadata framework. The survey consisted of 5-Likert multiple-choice questions and open-ended questions. Two more researchers were asked to use the metadata framework to annotate 8 type-2 diabetes mellitus phenotypes. More than 90% of the survey respondents rated metadata elements regarding phenotype definition and validation methods and metrics positively with a score of 4 or 5. Both researchers completed annotation of each phenotype within 60 min. Our thematic analysis of the narrative feedback indicates that the metadata framework was effective in capturing rich and explicit descriptions and enabling the search for phenotypes, compliance with data standards, and comprehensive validation metrics. Current limitations were its complexity for data collection and the entailed human costs.

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