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Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels
No full textBACKGROUND: The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. METHODS: We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1-5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP. RESULTS: Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81-0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools' training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64-0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset). CONCLUSIONS: Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.UnknownThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Selection of patients with malignant melanoma for pelvic lymph node dissection (PLND) using CT-PET
No full textOBJECTIVES: In melanoma patients with positive pelvic nodes, pelvic lymph node dissection (PLND) to achieve fully resected disease status facilitates adjuvant-dose systemic therapy and avoids higher treatment doses with greater toxicity. This study aimed to test the accuracy of prediction of nodal involvement of the 2010 joint BAPRAS/BAD guidance compared with Positron Emission Tomography (CT-PET). METHODS: A retrospective review was undertaken of 26 melanoma patients undergoing PLND by a single surgeon between July 2012 and July 2020. The indications for performing PLND were in accordance with the 2010 guidance, but this was supplemented by CT-PET in 16/26 patients. RESULTS: Of the 26 patients undergoing PLND, 10 underwent surgery based upon the 2010 criteria alone and 16 underwent supplementary CT-PET. 17 patients had positive nodes on histology; of these, 13 had a positive CT-PET. Amongst node-negative patients, only one had a false positive CT-PET. CT-PET was 100% sensitive for pelvic nodal disease and 75% specific, with a positive predictive value for nodal involvement of 92%. Of the 10 patients who underwent PLND without CT-PET, only 4 had positive nodes while 6 patients had negative nodes. CONCLUSIONS: The 2010 guidelines remain broad and contributed to negative PLND in a third of our patients (9/26). Hence, the indications for performing PLND need to be revisited. Our series supports PET-CT as being 100% sensitive in the identification of pelvic nodal disease and 75% specific. We recommend that a positive PET-CT should be considered as the primary indication for PLND in melanoma patients.Published version, accepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Utility of genetic risk scores in type 1 diabetes
No full textIterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong associations across the HLA class II region that account for >50% of heritability. The increased availability of genetic data combined with the decreased costs of generating these data, have facilitated the development of polygenic scores that aggregate risk variants from associated loci into a single number: either a genetic risk score (GRS) or a polygenic risk score (PRS). PRSs incorporate the risk of many possibly correlated variants from across the genome, even if they do not reach genome-wide significance, whereas GRSs estimate the cumulative contribution of a smaller subset of genetic variants that reach genome-wide significance. Type 1 diabetes GRSs have utility in diabetes classification, aiding discrimination between type 1 diabetes, type 2 diabetes and MODY. Type 1 diabetes GRSs are also being used in newborn screening studies to identify infants at risk of future presentation of the disease. Most early studies of type 1 diabetes genetics have been conducted in European ancestry populations, but, to develop accurate GRSs across diverse ancestries, large case-control cohorts from non-European populations are still needed. The current barriers to GRS implementation within healthcare are mainly related to a lack of guidance and knowledge on integration with other biomarkers and clinical variables. Once these limitations are addressed, there is huge potential for 'test and treat' approaches to be used to tailor care for individuals with type 1 diabetes.Published version, accepted version (12 month embargo)The article is available via Open Access. Click on the 'Additional link' above to access the full-text
Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders
No full textDespite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.Published version, accepted version (6 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Type 1 Diabetes Genetic Risk Score Differentiates Subgroups of Ketosis-Prone Diabetes
No full textOBJECTIVE: To determine whether genetic risk for type 1 diabetes (T1D) differentiates the four Aβ subgroups of ketosis-prone diabetes (KPD), where A+ and A- define the presence or absence of islet autoantibodies and β+ and β- define the presence or absence of β-cell function. RESEARCH DESIGN AND METHODS: We compared T1D genetic risk scores (GRSs) of patients with KPD across subgroups, race/ethnicity, β-cell function, and glycemia. RESULTS: Among 426 patients with KPD (54% Hispanic, 31% African American, 11% White), rank order of GRS was A+β- > A+β+ = A-β- > A-β+. GRS of A+β- KPD was lower than that of a T1D cohort, and GRS of A-β+ KPD was higher than that of a type 2 diabetes cohort. GRS was lowest among African American patients, with a similar distribution across KPD subgroups. CONCLUSIONS: T1D genetic risk delineates etiologic differences among KPD subgroups. Patients with A+β- KPD have the highest and those with A-β+ KPD the lowest GRS.Accepted version, submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Creating a collaborative network in a low/middle income country region. A practical (and motivational) guide to getting started
No full textAccepted version (12 month embargo)RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Does correction of carpal malalignment influence the union rate of scaphoid nonunion surgery?
No full textThe aim of this retrospective study was to assess the relation between carpal malalignment correction and radiological union rates in surgery for scaphoid nonunions. A total of 59 scaphoid waist fracture nonunions treated with open reduction and palmar tricortical autograft were divided according to their pre- and postoperative scapholunate (SL) and radiolunate (RL) angles. We found that carpal malalignment failed to correct in 32 of 59 (54.2%) patients despite meticulous surgical technique and placement of an appropriately sized wedge-shaped graft. In total, 43 (72.9%) fractures united at a mean of 4.47 months (range 3-11). Of the 27 fractures with postoperative SL and RL angles within the normal range, 21 united, whereas 22 of the 32 remaining fractures that failed to achieve postoperative angles within the normal range went on to union. The postoperative SL and RL angles were not related to union. Our findings suggest that in scaphoid fracture nonunion surgery, carpal malalignment may not be corrected in a substantial proportion of patients, but such correction may not be essential for bony union. Our findings also show that there is no marked collapse of the scaphoid graft in the early postoperative period. LEVEL OF EVIDENCE: IV.Published version, accepted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Preoperative intravenous iron and the risk of blood transfusion in colorectal cancer surgery: meta-analysis of randomized clinical trials
No full textPublished version, accepted version (12 month embargo), submitted versionRD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The effect of cisplatin-based neoadjuvant chemotherapy on the renal function of patients undergoing radical cystectomy
No full textINTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m(2) reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m(2) (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m(2)) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m(2)). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m(2)), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year.UnknownSupports Open Acces