17 research outputs found

    Identifying patients with undiagnosed small intestinal neuroendocrine tumours in primary care using statistical and machine learning: model development and validation study

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    Background: Neuroendocrine tumours (NETs) are increasing in incidence, often diagnosed at advanced stages, and individuals may experience years of diagnostic delay, particularly when arising from the small intestine (SI). Clinical prediction models could present novel opportunities for case finding in primary care. Methods: An open cohort of adults (18+ years) contributing data to the Optimum Patient Care Research Database between 1st Jan 2000 and 30th March 2023 was identified. This database collects de-identified data from general practices in the UK. Model development approaches comprised logistic regression, penalised regression, and XGBoost. Performance (discrimination and calibration) was assessed using internal-external cross-validation. Decision analysis curves compared clinical utility. Results: Of 11.7 million individuals, 382 had recorded SI NET diagnoses (0.003%). The XGBoost model had the highest AUC (0.869, 95% confidence interval [CI]: 0.841–0.898) but was mildly miscalibrated (slope 1.165, 95% CI: 1.088–1.243; calibration-in-the-large 0.010, 95% CI: −0.164 to 0.185). Clinical utility was similar across all models. Discussion: Multivariable prediction models may have clinical utility in identifying individuals with undiagnosed SI NETs using information in their primary care records. Further evaluation including external validation and health economics modelling may identify cost-effective strategies for case finding for this uncommon tumour

    Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition

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    Dravet syndrome is an archetypal rare severe epilepsy, considered “monogenic”, typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

    Supplementary data for "The diagnostic odyssey in children and adolescents with X-linked hypophosphataemia: population-based, case-control study"

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    This study explored the recording of clinical features and the diagnostic odyssey of children and adolescents with X-linked hypophosphataemia in primary care electronic healthcare records in the United Kingdom.</p

    Functional Analysis of a Carotid Intima-Media Thickness Locus Implicates <i>BCAR1</i> and Suggests a Causal Variant

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    Background— Carotid intima-media thickness (IMT) is a marker of subclinical atherosclerosis that can predict cardiovascular disease events over traditional risk factors. This study examined the BCAR1-CFDP1-TMEM170A locus on chromosome 16, associated with carotid IMT and coronary artery disease in the IMT and IMT-Progression as Predictors of Vascular Events (IMPROVE) cohort, to identify the functional variant. Methods and Results— In analysis of the locus lead single nucleotide polymorphism (SNP; rs4888378, intronic in CFDP1 ) in Progressione della Lesione Intimale Carotidea (PLIC), the protective AA genotype was associated with slower IMT progression in women ( P =0.04) but not in men. Meta-analysis of 5 cohort studies also supported a protective effect of the A allele on common carotid IMT in women only (women: ÎČ=−0.0047, P =1.63×10 –4 ; men: ÎČ=−0.0029, P =0.0678). Two hundred fourteen noncoding variants in strong linkage disequilibrium ( r 2 ≄0.8) with rs4888378 were identified from 1000 Genome Project. ENCODE regulatory chromatin marks were used to create a shortlist of 6 possible regulatory variants. Electrophoretic mobility shift assays on the shortlist detected allele-specific protein binding to the lead SNP rs4888378; multiplexed competitor electrophoretic mobility shift assays implicated FOXA as the protein. Luciferase reporter assays on rs4888378 showed a significant 35% to 92% ( P =0.0057; P =4.0×10 –22 ) decrease in gene expression with the A allele. Expression quantitative trait loci analysis confirmed previously reported associations of rs4888378 with BCAR1 in vascular tissues. Conclusions— Molecular studies suggest the lead SNP as a potentially causal SNP at the BCAR1 - CFDP1 - TMEM170A locus, and expression quantitative trait loci studies implicate BCAR1 as the causal gene. This variant showed stronger effects on common carotid IMT in women, raising questions about the mechanism of the causal SNP on atherosclerosis. </jats:sec

    Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations

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    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs
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