ORCID Profile
0000-0002-6133-0164
Current Organisations
Dana Farber Cancer Institute
,
University of Oxford
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Publisher: BMJ
Date: 27-08-2020
DOI: 10.1136/GUTJNL-2020-321650
Abstract: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2–6 months in the 2WW pathway. We stratified by age group, in idual-level benefit in CRC survival versus age-specific nosocomial COVID-19–related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008–2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk–benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged . Prioritisation out of delay for the 18% of symptomatic referrals with FIT µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by %. Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
Publisher: Elsevier BV
Date: 10-2017
Publisher: American Society of Hematology
Date: 08-11-2018
DOI: 10.1182/BLOOD-2018-06-855296
Abstract: To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775 P = 2.11 × 10−10), 6q23.3 (rs1002658 P = 2.97 × 10−8), 11q23.1 (rs7111520 P = 1.44 × 10−11), 16p11.2 (rs6565176 P = 4.00 × 10−8), and 20q13.12 (rs2425752 P = 2.01 × 10−8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-κB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2018
DOI: 10.1038/S41467-018-04989-W
Abstract: Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
Publisher: Wiley
Date: 07-2019
DOI: 10.1111/ANDR.12667
Abstract: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. To examine whether RoH are associated with TGCT risk. We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. Global measures of homozygosity were not significantly different between cases and controls, and the frequency of in idual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2019
DOI: 10.1038/S41467-018-08107-8
Abstract: The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article the PDF version was correct at the time of publication.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2019
DOI: 10.1038/S41467-019-09775-W
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
Publisher: Cold Spring Harbor Laboratory
Date: 05-05-2020
DOI: 10.1101/2020.04.28.20083170
Abstract: The COVID-19 pandemic has caused disruption across cancer pathways for diagnosis and treatment. In England, 32% of colorectal cancer (CRC) is diagnosed via urgent symptomatic referral from primary care, the “2-week-wait” (2WW) pathway. Access to routine endoscopy is likely to be a critical bottleneck causing delays in CRC management due to chronic limitation in capacity, acute competition for physician time, and safety concerns. We used age-specific, stage-specific 10 year CRC survival for England 2007–2017 and 2WW CRC cases volumes. We used per-day hazard ratios of CRC survival generated from observational studies of CRC diagnosis-to-treatment interval to model the effect of different durations of per-patient delay. We utilised data from a large London observational study of faecal immunochemical testing (FIT) in symptomatic patients to model FIT-triage to mitigate delay to colonoscopy. Modest delays result in significant reduction in survival from CRC with a 4-month delay resulting across age groups in ≥20% reduction in survival in Stage 3 disease and in total over a year, 1,419 attributable deaths across the 11,266 CRC patients diagnosed via the 2WW pathway. FIT triage of ug Hb/g would salvage 1,292/1,419 of the attributable deaths and reduce colonoscopy requirements by %. Diagnostic colonoscopy offers net survival in all age groups, providing nosocomial COVID-19 infection rates are kept low ( ·5%). To avoid significant numbers of avoidable deaths from CRC, normal diagnostic and surgical throughput must be maintained. An accrued backlog of cases will present to primary care following release of lockdown, supranormal endoscopy capacity will be required to manage this without undue delays. FIT-triage of symptomatic cases provides a rational approach by which to avoid patient delay and mitigate pressure on capacity in endoscopy. This would also reduce exposure to nosocomial COVID-19 infection, relevant in particular to older patient groups. Breast Cancer Now, Cancer Research UK, Bobby Moore Fund for Cancer Research, National Institute for Health Research (NIHR).
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
DOI: 10.1038/S41467-018-08105-W
Abstract: The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1186/S12872-019-1187-Z
Abstract: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Published and in idual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57 1.22) for the GS, compared to 0.85 (95% CI 0.78 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11 1.50) for the GS, as compared to 1.00 (95% CI 0.96 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown although precision was moderate.
Publisher: Wiley
Date: 06-04-2017
DOI: 10.1002/IJC.30709
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: No location found
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Amit Sud.