Imperial College London

DrCliveHoggart

Faculty of MedicineDepartment of Infectious Disease

Honorary Research Officer
 
 
 
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+44 (0)20 7594 3915c.hoggart

 
 
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231Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

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74 results found

Hoggart CJ, Choi SW, García-González J, Souaiaia T, Preuss M, O'Reilly PFet al., 2024, BridgePRS leverages shared genetic effects across ancestries to increase polygenic risk score portability., Nat Genet, Vol: 56, Pages: 180-186

Here we present BridgePRS, a novel Bayesian polygenic risk score (PRS) method that leverages shared genetic effects across ancestries to increase PRS portability. We evaluate BridgePRS via simulations and real UK Biobank data across 19 traits in individuals of African, South Asian and East Asian ancestry, using both UK Biobank and Biobank Japan genome-wide association study summary statistics; out-of-cohort validation is performed in the Mount Sinai (New York) BioMe biobank. BridgePRS is compared with the leading alternative, PRS-CSx, and two other PRS methods. Simulations suggest that the performance of BridgePRS relative to PRS-CSx increases as uncertainty increases: with lower trait heritability, higher polygenicity and greater between-population genetic diversity; and when causal variants are not present in the data. In real data, BridgePRS has a 61% larger average R2 than PRS-CSx in out-of-cohort prediction of African ancestry samples in BioMe (P = 6 × 10-5). BridgePRS is a computationally efficient, user-friendly and powerful approach for PRS analyses in non-European ancestries.

Journal article

Lennon NJ, Kottyan LC, Kachulis C, Abul-Husn N, Arias J, Belbin G, Below JE, Berndt S, Chung W, Cimino JJ, Clayton EW, Connolly JJ, Crosslin D, Dikilitas O, Velez Edwards DR, Feng Q, Fisher M, Freimuth R, Ge T, GIANT Consortium, All of Us Research Program, Glessner JT, Gordon A, Guiducci C, Hakonarson H, Harden M, Harr M, Hirschhorn J, Hoggart C, Hsu L, Irvin R, Jarvik GP, Karlson EW, Khan A, Khera A, Kiryluk K, Kullo I, Larkin K, Limdi N, Linder JE, Loos R, Luo Y, Malolepsza E, Manolio T, Martin LJ, McCarthy L, Meigs JB, Mersha TB, Mosley J, Namjou B, Pai N, Pesce LL, Peters U, Peterson J, Prows CA, Puckelwartz MJ, Rehm H, Roden D, Rosenthal EA, Rowley R, Sawicki KT, Schaid D, Schmidlen T, Smit R, Smith J, Smoller JW, Thomas M, Tiwari H, Toledo D, Vaitinadin NS, Veenstra D, Walunas T, Wang Z, Wei W-Q, Weng C, Wiesner G, Xianyong Y, Kenny Eet al., 2023, Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations., medRxiv

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.

Journal article

Channon-Wells S, Vito O, McArdle AJ, Seaby EG, Patel H, Shah P, Pazukhina E, Wilson C, Broderick C, D'Souza G, Keren I, Nijman RG, Tremoulet A, Munblit D, Ulloa-Gutierrez R, Carter MJ, Ramnarayan P, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Blyuss O, Levin M, Chouli M, Hamadouche N, Ladj MS, Agrimbau Vázquez J, Carmona R, Collia AG, Ellis A, Natta D, Pérez L, Rubiños M, Veliz N, Yori S, Britton PN, Burgner DP, Carey E, Crawford NW, Giuliano H, McMinn A, Wong S, Wood N, Holter W, Krainz M, Ulreich R, Zurl C, Dehoorne J, Haerynck F, Hoste L, Schelstraete P, Vandekerckhove K, Willems J, Almeida Farias CG, Almeida FJ, Alves Leal I, Araujo da Silva AR, Araujo e Silva AE, Barreiro STA, Bomfim Prado da Silva DG, Cervi MC, dos Santos Naja Cardoso MV, Henriques Teixeira C, Jarovsky D, Martins Araujo J, Naaman Berezin E, Palazzi Sáfadi MA, Paternina-de la Ossa RA, Souza Vieira C, Dimitrova A, Ganeva M, Stefanov S, Telcharova-Mihaylovska A, Biggs CM, Lopez A, Scuccimarri R, Tan R, Wasserman S, Withington D, Ampuero C, Aravena J, Bustos B R, Casanova D, Cruces P, Diaz F, García-Salum T, Godoy L, Medina RA, Valenzuela Galaz G, Camacho-Moreno G, Avila-Aguero ML, Brenes-Chacón H, Camacho-Badilla K, Ivankovich-Escoto G, Naranjo-Zuniga G, Soriano-Fallas A, Ulloa-Gutierrez R, Yock-Corrales A, Amer MA, Abdelmeguid Y, Ahmed YHHZ, Badib A, Badreldin K, Elkhashab Y, Heshmat H, Hussein A, Mohamed Hussein AH, Ibrahim S, Shoman W, Yakout RM, Heinonen S, Angoulvant F, Belot A, Ouldali N, Beske F, Heep A, Masjosthusmann K, Reiter K, van den Heuvel I, von Both U, Agrafiotou A, Antachopoulos C, Charisi K, Eleftheriou I, Farmaki E, Fotis L, Kafetzis D, Koletsi P, Kourtesi K, Lampidi S, Liakopoulou T, Maritsi D, Michailidou E, Milioudi M, Mparmpounaki I, Papadimitriou E, Papaevangelou V, Roilides E, Tsiatsiou O, Tsolas G, Tsolia M, Vantsi P, Banegas Pineda LY, Borjas Aguilar KL, Cantillano Quintero EM, Ip P, Kwan MYW, Kwok J, Lau YL, To K, Wong JSC, David M, Farkas D, Kaet al., 2023, Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study, The Lancet Rheumatology, Vol: 5, Pages: e184-e199, ISSN: 2665-9913

BackgroundMultisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.MethodsThe Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370.FindingsWe enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologica

Journal article

Hoggart C, Choi SW, García-González J, Souaiaia T, Preuss M, O'Reilly Pet al., 2023, BridgePRS : A powerful trans-ancestry Polygenic Risk Score method., bioRxiv

Polygenic Risk Scores (PRS) have huge potential to contribute to biomedical research and to a future of precision medicine, but to date their calculation relies largely on Europeanancestry GWAS data. This global bias makes most PRS substantially less accurate in individuals of non-European ancestry. Here we present BridgePRS , a novel Bayesian PRS method that leverages shared genetic effects across ancestries to increase the accuracy of PRS in non-European populations. The performance of BridgePRS is evaluated in simulated data and real UK Biobank (UKB) data across 19 traits in African, South Asian and East Asian ancestry individuals, using both UKB and Biobank Japan GWAS summary statistics. BridgePRS is compared to the leading alternative, PRS-CSx , and two single-ancestry PRS methods adapted for trans-ancestry prediction. PRS trained in the UK Biobank are then validated out-of-cohort in the independent Mount Sinai (New York) Bio Me Biobank. Simulations reveal that BridgePRS performance, relative to PRS-CSx , increases as uncertainty increases: with lower heritability, higher polygenicity, greater between-population genetic diversity, and when causal variants are not present in the data. Our simulation results are consistent with real data analyses in which BridgePRS has better predictive accuracy in African ancestry samples, especially in out-of-cohort prediction (into Bio Me ), which shows a 60% boost in mean R 2 compared to PRS-CSx ( P = 2 × 10 -6 ). BridgePRS performs the full PRS analysis pipeline, is computationally efficient, and is a powerful method for deriving PRS in diverse and under-represented ancestry populations.

Journal article

Kuiper R, Wright VJ, Habgood-Coote D, Shimizu C, Huigh D, Tremoulet AH, van Keulen D, Hoggart CJ, Rodriguez-Manzano J, Herberg JA, Kaforou M, Tempel D, Burns JC, Levin Met al., 2023, Bridging a diagnostic Kawasaki disease classifier from a microarray platform to a qRT-PCR assay, Pediatric Research, Vol: 93, Pages: 559-569, ISSN: 0031-3998

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier. METHODS: We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier. RESULTS: The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections. CONCLUSION: We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory. IMPACT: A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.

Journal article

Choi SW, Garcia-Gonzalez J, Ruan Y, Wu HM, Porras C, Johnson J, Hoggart C, O'Reilly Pet al., 2023, PRSet: Pathway-based polygenic risk score analyses and software, PLOS GENETICS, Vol: 19, ISSN: 1553-7404

Journal article

Kumar V, Pouw RB, Autio M, Sagmeister MG, Phua ZY, Borghini L, Wright VJ, Hoggart C, Pan B, Tan AKY, Binder A, Brouwer MC, Pinnock E, De Groot R, Hazelzet J, Emonts M, van der Flier M, Reiter K, Nothen MM, Hoffmann P, Schlapbach LJ, Bellos E, Anderson S, Secka F, Martinon-Torres F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Zenz W, Wouters D, Ang LT, Hibberd ML, Levin M, Kuijpers TW, Davila Set al., 2022, Variation in <i>CFHR3</i> determines susceptibility to meningococcal disease by controlling factor H concentrations, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 1680-1691, ISSN: 0002-9297

Journal article

Pathak GA, Polimanti R, Karjalainen J, Daly M, Ganna A, Daly MJ, Stevens C, Kanai M, Liao RG, Trankiem A, Balaconis MK, Nguyen H, Solomonson M, Veerapen K, Ripatti S, Nkambul L, Bryant S, Sankaran VG, Neale BM, Karczewski KJ, Martin AR, Atkinson EG, Tsuo K, Baya N, Turley P, Gupta R, Walters RK, Palmer DS, Sarma G, Cheng N, Lu W, Churchhouse C, Goldstein J, King D, Zhou W, Seed C, Finucane H, Satterstrom FK, Andrews SJ, Sloofman LG, Sealfon SC, Hoggart C, Underwood SJ, Cordioli M, Pirinen M, Donner K, Kivinen K, Palotie A, Kaunisto M, Harerimana N, Chwialkowska K, Wolford B, Roberts G, Park D, Ball CA, Coignet M, McCurdy S, Knight S, Partha R, Rhead B, Zhang M, Berkowitz N, Gaddis M, Noto K, Ruiz L, Pavlovic M, Hong EL, Rand K, Girshick A, Guturu H, Baltzell AH, Niemi MEK, Pigazzini S, Rahmouni S, Georges M, Belhaj Y, Guntz J, Claassen S, Beguin Y, Gofflot S, Nkambule L, Nkambul L, Cusick C, Moutschen M, Misset B, Darcis G, Guiot J, Azarzar S, Malaise O, Huynen P, Meuris C, Thys M, Jacques J, Leonard P, Frippiat F, Giot J-B, Sauvage A-S, Von Frenckell C, Lambermont B, Nakanishi T, Morrison DR, Richards JB, Butler-Laporte G, Forgetta V, Ghosh B, Laurent L, Henry D, Abdullah T, Adeleye O, Mamlouk N, Kimchi N, Afrasiabi Z, Rezk N, Vulesevic B, Bouab M, Guzman C, Petitjean L, Tselios C, Xue X, Afilalo J, Adra D, Mooser V, Li R, Belisle A, Lepage P, Ragoussis J, Auld D, Lathrop GM, Afilalo M, Oliveira M, Brenner B, Brassard N, Durand M, Chasse M, Kaufmann DE, Schurr E, Hayward C, Richmond A, Baillie JK, Glessner JT, Hakonarson H, Chang X, Shaw DM, Below J, Polikowski H, Lauren PE, Chen H-H, Zhu W, Davis L, Kerchberger VE, Campbell A, Porteous DJ, Fawns-Ritchie C, Morris M, McCormick JB, North K, Glessner JR, Gignoux CR, Wicks SJ, Crooks K, Barnes KC, Daya M, Shortt J, Rafaels N, Chavan S, Timmers PRHJ, Wilson JF, Tenesa A, Kerr SM, D'Mellow K, Shahin D, El-Sherbiny YM, El-Jawhari JJ, von Hohenstaufen KA, Sobh A, Eltoukhy MM, Mohamed AAS, Elhadidy TA, Abd Elghafar MS, Elnet al., 2022, A first update on mapping the human genetic architecture of COVID-19, NATURE, Vol: 608, Pages: E1-E10, ISSN: 0028-0836

Journal article

van Beek AE, Pouw RB, Wright VJ, Sallah N, Inwald D, Hoggart C, Brouwer MC, Galassini R, Thomas J, Calvo-Bado L, Fink CG, Jongerius I, Hibberd M, Wouters D, Levin M, Kuijpers TWet al., 2022, Low levels of factor H family proteins during meningococcal disease indicate systemic processes rather than specific depletion by neisseria meningitidis, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224

Neisseria meningitidis, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that the circulating levels of all FH family proteins, not only FH and FHR-3, are equally decreased during the acute illness. We did neither observe specific consumption of FH or FHR-3 by N. meningitidis, nor of any of the other FH family proteins, suggesting that the globally reduced levels are due to systemic processes including dilution by fluid administration upon admission and vascular leakage. MD severity associated predominantly with a loss of FH rather than FHRs. Additionally, low FH levels associated with renal failure, suggesting insufficient protection of host tissue by the active protection by the FH protein family, which is reminiscent of reduced FH activity in hemolytic uremic syndrome. Retaining higher levels of FH may thus limit tissue injury during MD.

Journal article

Prive F, Aschard H, Carmi S, Folkersen L, Hoggart C, O'Reilly PF, Vilhjalmsson BJet al., 2022, Portability of 245 polygenic scores when to 9 ancestry groups from the same cohort (vol 109, pg 12, 2022), AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 373-373, ISSN: 0002-9297

Journal article

Hoggart C, Shimizu C, Galassini R, Wright VJ, Shailes H, Bellos E, Herberg JA, Pollard AJ, O'Connor D, Choi SW, Seaby EG, Menikou S, Hibberd M, Sallah N, Burgner D, Brogan P, Patel H, Kim J, Tremoulet AH, Salo E, van Stijn D, Kuijpers T, Burns JC, Levin Met al., 2021, Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease, European Journal of Human Genetics, Vol: 29, Pages: 1734-1744, ISSN: 1018-4813

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, Broderick C, Nijman R, Tremoulet AH, Munblit D, Ulloa-Gutierrez R, Carter MJ, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Levin Met al., 2021, Treatment of multisystem inflammatory syndrome in children, New England Journal of Medicine, Vol: 385, Pages: 11-22, ISSN: 0028-4793

BACKGROUNDEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODSWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTSData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONSWe found n

Journal article

Morris TC, Hoggart CJ, Chegou NN, Kidd M, Oni T, Goliath R, Wilkinson KA, Dockrell HM, Sichali L, Banda L, Crampin AC, French N, Walzl G, Levin M, Wilkinson RJ, Hamilton MSet al., 2021, Evaluation of host serum protein biomarkers of tuberculosis in sub-Saharan Africa, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224

Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity for Mycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.

Journal article

Togun T, Hoggart CJ, Agbla SC, Gomez MP, Egere U, Sillah AK, Saidy B, Mendy F, Pai M, Kampmann Bet al., 2020, A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children, EBIOMEDICINE, Vol: 58, ISSN: 2352-3964

Journal article

Choi J, Zhang T, Vu A, Ablain J, Makowski MM, Colli LM, Xu M, Hennessey RC, Yin J, Rothschild H, Grawe C, Kovacs MA, Funderburk KM, Brossard M, Taylor J, Pasaniuc B, Chari R, Chanock SJ, Hoggart CJ, Demenais F, Barrett JH, Law MH, Iles MM, Yu K, Vermeulen M, Zon L, Brown KMet al., 2020, Massively parallel reporter assays of melanoma risk variants identify <i>MX2</i> as a gene promoting melanoma, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723

Journal article

David A, 2020, A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin, Molecular Genetics and Genomic Medicine, Vol: 8, Pages: 1-9, ISSN: 2324-9269

BackgroundSevere hypercholesterolemia (HC, LDL‐C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL‐C.MethodsSummary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used.ResultsA 36‐SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL‐C trait and explained 8% of its variability (p = 10–41). After risk categorization, the risk of having HC was higher in the high‐ versus low‐risk group (RR = 4.17, p < 1 × 10−7). Compared to a 12‐SNP LDL‐C raising score (currently used in the United Kingdom), the PRS explained more LDL‐C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL‐C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL‐C raising score were reclassified to intermediate or high risk by the new PRS.ConclusionThe new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms.

Journal article

Leal Ayala LG, David A, Jarvelin MR, Sebert S, Ruddock M, Karhunen V, Seaby E, Hoggart C, Sternberg MJEet al., 2019, Identification of disease-associated loci using machine learning for genotype and network data integration, Bioinformatics, Vol: 35, Pages: 5182-5190, ISSN: 1367-4803

MotivationIntegration of different omics data could markedly help to identify biological signatures, understand the missing heritability of complex diseases and ultimately achieve personalized medicine. Standard regression models used in Genome-Wide Association Studies (GWAS) identify loci with a strong effect size, whereas GWAS meta-analyses are often needed to capture weak loci contributing to the missing heritability. Development of novel machine learning algorithms for merging genotype data with other omics data is highly needed as it could enhance the prioritization of weak loci.ResultsWe developed cNMTF (corrected non-negative matrix tri-factorization), an integrative algorithm based on clustering techniques of biological data. This method assesses the inter-relatedness between genotypes, phenotypes, the damaging effect of the variants and gene networks in order to identify loci-trait associations. cNMTF was used to prioritize genes associated with lipid traits in two population cohorts. We replicated 129 genes reported in GWAS world-wide and provided evidence that supports 85% of our findings (226 out of 265 genes), including recent associations in literature (NLGN1), regulators of lipid metabolism (DAB1) and pleiotropic genes for lipid traits (CARM1). Moreover, cNMTF performed efficiently against strong population structures by accounting for the individuals’ ancestry. As the method is flexible in the incorporation of diverse omics data sources, it can be easily adapted to the user’s research needs.

Journal article

Wang X, Nijman R, Camuzeaux S, Sands C, Jackson H, Kaforou M, Emonts M, Herberg J, Maconochie I, Carrol E, Paulus S, Zenz W, Coin L, Flier MVD, Groot RD, Martinon-Torres F, Schlapbach LJ, Pollard A, Fink C, Kuijpers TT, Anderson S, Lewis M, Levin M, McClure M, EUCLIDS consortiumet al., 2019, Plasma lipid profiles discriminate bacterial from viral infection in febrile children, Scientific Reports, Vol: 9, ISSN: 2045-2322

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group..A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

Journal article

Levin M, Cunnington AJ, Hoggart CJ, 2019, Secondary re-analysis of the FEAST trial - Authors' reply, The Lancet Respiratory Medicine, Vol: 7, Pages: e31-e31, ISSN: 2213-2600

Journal article

Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ, Ninis N, McCulloch M, Argent A, Buys H, Moxon CA, Best A, Nijman RG, Hoggart CJet al., 2019, Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial, Lancet Respiratory Medicine, Vol: 7, Pages: 581-593, ISSN: 2213-2600

BACKGROUND: Fluid resuscitation is the recommended management of shock, but increased mortality in febrile African children in the FEAST trial. We hypothesised that fluid bolus-induced deaths in FEAST would be associated with detectable changes in cardiovascular, neurological, or respiratory function, oxygen carrying capacity, and blood biochemistry. METHODS: We developed composite scores for respiratory, cardiovascular, and neurological function using vital sign data from the FEAST trial, and used them to compare participants from FEAST with those from four other cohorts and to identify differences between the bolus (n=2097) and no bolus (n=1044) groups of FEAST. We calculated the odds of adverse outcome for each ten-unit increase in baseline score using logistic regression for each cohort. Within FEAST participants, we also compared haemoglobin and plasma biochemistry between bolus and non-bolus patients, assessed the effects of these factors along with the vital sign scores on the contribution of bolus to mortality using Cox proportional hazard models, and used Bayesian clustering to identify subgroups that differed in response to bolus. The FEAST trial is registered with ISRCTN, number ISRCTN69856593. FINDINGS: Increasing respiratory (odds ratio 1·09, 95% CI 1·07-1·11), neurological (1·26, 1·21-1·31), and cardiovascular scores (1·09, 1·05-1·14) were associated with death in FEAST (all p<0·0001), and with adverse outcomes for specific scores in the four other cohorts. In FEAST, fluid bolus increased respiratory and neurological scores and decreased cardiovascular score at 1 h after commencement of the infusion. Fluid bolus recipients had mean 0·33 g/dL (95% CI 0·20-0·46) reduction in haemoglobin concentration after 8 h (p<0·0001), and at 24 h had a decrease of 1·41 mEq/L (95% CI 0·76-2·06; p=0·0002) in mean base excess and increase o

Journal article

O'Connor D, Png E, Khor CC, Snape MD, Hil AVS, van der Klis F, Hoggart C, Levin M, Hibberd ML, Pollard AJet al., 2019, Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization, CELL REPORTS, Vol: 27, Pages: 3241-+, ISSN: 2211-1247

Journal article

Borghini L, Png E, Binder A, Wright VJ, Pinnock E, de Groot R, Hazelzet J, Emonts M, Van der Flier M, Schlapbach LJ, Anderson S, Secka F, Salas A, Fink C, Carrol ED, Pollard AJ, Coin LJ, Kuijpers TW, Martinon-Torres F, Zenz W, Levin M, Hibberd ML, Davila S, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Abdulla A, Agapow P, Bartlett M, Bellos E, Eleftherohorinou H, Galassini R, Inwald D, Mashbat M, Menikou S, Mustafa S, Nadel S, Rahman R, Thakker C, Bokhandi S, Power S, Barham H, Pathan N, Ridout J, White D, Thurston S, Faust S, Patel S, McCorkell J, Davies P, Cratev L, Navarra H, Carter S, Ramaiah R, Patel R, Tuffrey C, Gribbin A, McCready S, Peters M, Hardy K, Standing F, O'Neill L, Abelake E, Deep A, Nsirim E, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Alvez Gonzalez F, Barral-Arca R, Cebey-Lopez M, Jose Curras-Tuala M, Garcia N, Garcia Vicente L, Gomez-Carballa A, Gomez Rial J, Grela Beiroa A, Justicia Grande A, Leborans Iglesias P, Martinez Santos AE, Martinon-Torres N, Martinon Sanchez JM, Mosquera Perez B, Obando Pacheco P, Pardo-Seco J, Pischedda S, Rivero Calle I, Rodriguez-Tenreiro C, Redondo-Collazo L, Seren Fernandez S, Porto Silva MDS, Vega A, Beatriz Reyes S, Leon Leon MC, Navarro Mingorance A, Gabaldo Barrios X, Onate Vergara E, Concha Torre A, Vivanco A, Fernandez R, Gimenez Sanchez F, Sanchez Forte M, Rojo P, Ruiz Contreras J, Palacios A, Navarro M, Alvarez Alvarez C, Jose Lozano M, Carreras E, Brio Sanagustin S, Neth O, Martinez Padilla MDC, Prieto Tato LM, Guillen S, Fernandez Silveira L, Moreno D, van Furth AMT, van der Flier M, Boeddha NP, Driessen GJA, Pajkrt D, Sanders EAM, van de Beek D, van der Ende A, Philipsen HLA, Adeel AOA, Breukels MA, Brinkman DMC, de Korte CCMM, de Vries E, de Waal WJ, Dekkers R, Dings-Lammertink A, Doedens RA, Donker AE, Dousma M, Faber TE, Gerrits GPJM, Gerver JAM, Heidema J, Homan-van der Veen J, Jacobs MAM, Jansen NJG, Kawczynski P, Klucovska K, Kneyber MCJ Ket al., 2019, Identification of regulatory variants associated with genetic susceptibility to meningococcal disease, Scientific Reports, Vol: 9, ISSN: 2045-2322

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Journal article

Cust AE, Drummond M, Kanetsky PA, Goldstein AM, Barrett JH, MacGregor S, Law MH, Iles MM, Bui M, Hopper JL, Brossard M, Demenais F, Taylor JC, Hoggart C, Brown KM, Landi MT, Newton-Bishop JA, Mann GJ, Bishop DTet al., 2018, Assessing the incremental contribution of common genomic variants to melanoma risk prediction in two population-based studies, Journal of Investigative Dermatology, Vol: 138, Pages: 2617-2624, ISSN: 0022-202X

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

Journal article

Wright V, Herberg J, Kaforou M, Shimizu C, Eleftherohorinou H, Shailes H, Barendregt A, Menikou S, Gormley S, Berk M, Hoang L, Tremoulet A, Kanegaye J, Coin L, Glode M, Hibberd M, Kuijpers T, Hoggart C, Burns J, Levin Met al., 2018, Diagnosis of Kawasaki disease using a minimal whole blood gene expression signature, JAMA Pediatrics, Vol: 172, Pages: 1-10, ISSN: 2168-6203

Importance There is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms. Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness. Setting Hospitals in the UK, Spain, Netherlands and USA.Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index. Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defin

Journal article

Shao H, Ganesamoorthy D, Duarte T, Minh DC, Hoggart CJ, Coin LJMet al., 2018, nplnv: accurate detection and genotyping of inversions using long read sub-alignment, BMC Bioinformatics, Vol: 19, ISSN: 1471-2105

BackgroundDetection of genomic inversions remains challenging. Many existing methods primarily target inzversions with a non repetitive breakpoint, leaving inverted repeat (IR) mediated non-allelic homologous recombination (NAHR) inversions largely unexplored.ResultWe present npInv, a novel tool specifically for detecting and genotyping NAHR inversion using long read sub-alignment of long read sequencing data. We benchmark npInv with other tools in both simulation and real data. We use npInv to generate a whole-genome inversion map for NA12878 consisting of 30 NAHR inversions (of which 15 are novel), including all previously known NAHR mediated inversions in NA12878 with flanking IR less than 7kb. Our genotyping accuracy on this dataset was 94%. We used PCR to confirm the presence of two of these novel inversions. We show that there is a near linear relationship between the length of flanking IR and the minimum inversion size, without inverted repeats.ConclusionThe application of npInv shows high accuracy in both simulation and real data. The results give deeper insight into understanding inversion.

Journal article

Martinón-Torres F, Salas A, Rivero-Calle I, Cebey-López M, Pardo-Seco J, Herberg JA, Boeddha NP, Klobassa DS, Secka F, Paulus S, de Groot R, Schlapbach LJ, Driessen GJ, Anderson ST, Emonts M, Zenz W, Carrol ED, Van der Flier M, Levin M, Levin M, Coin L, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Wright V, Abdulla A, Agapow P, Bartlett M, Bellos E, Eleftherohorinou H, Galassini R, Inwald D, Mashbat M, Menikou S, Mustafa S, Nadel S, Rahman R, Thakker C, Bokhandi S, Power S, Barham H, Pathan N, Ridout J, White D, Thurston S, Faust S, Patel S, McCorkell J, Davies P, Crate L, Navarra H, Carter S, Ramaiah R, Patel R, Tuffrey C, Gribbin A, McCready S, Peters M, Hardy K, Standing F, O'Neill L, Abelake E, Deep A, Nsirim E, Pollard A, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Martinón-Torres F, Salas Ellacuriaga A, Álvez González F, Barral-Arca R, Cebey-López M, Curras-Tuala MJ, García N, García Vicente L, Gómez-Carballa A, Gómez Rial J, Grela Beiroa A, Justicia Grande A, Leboráns Iglesias P, Martínez Santos AE, Martinón-Torres N, Martinón Sánchez JM, Morillo Gutiérrez Bet al., 2018, Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study, Lancet Child and Adolescent Health, Vol: 2, Pages: 404-414, ISSN: 2352-4642

Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p < 0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%] ), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%] ), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admis

Journal article

Mobula LM, MacDermott NE, Hoggart C, Brantly K, Plyler L, Brown J, Kauffeldt B, Eisenhut D, Cooper LA, Fankhauser Jet al., 2018, Clinical manifestations and modes of death among Ebola Virus disease patients, Monrovia, Liberia, 2014, American Journal of Tropical Medicine and Hygiene, Vol: 98, Pages: 1186-1193, ISSN: 0002-9637

Although the high case fatality rate (CFR) associated with Ebola virus disease (EVD) is well documented, there are limited data on the actual modes of death. We conducted a retrospective, observational cohort study among patients with laboratory-confirmed EVD. The patients were all seen at the Eternal Love Winning Africa Ebola Treatment Unit in Monrovia, Liberia, from June to August 2014. Our primary objective was to describe the modes of death of our patients and to determine predictors of mortality. Data were available for 53 patients with laboratory-confirmed EVD, with a median age of 35 years. The most frequent presenting symptoms were weakness (91%), fever (81%), and diarrhea (78%). Visible hemorrhage was noted in 25% of the cases. The CFR was 79%. Odds of death were higher in patients with diarrhea (odds ratio = 26.1, P < 0.01). All patients with hemorrhagic signs died (P < 0.01). Among the 18 fatal cases for which clinical information was available, three distinct modes of death were observed: sudden death after a moderate disease process (44%), profuse hemorrhage (33%), and encephalopathy (22%). We found that these modes of death varied by age (P = 0.04), maximum temperature (P = 0.43), heart rate on admission (P = 0.04), time to death from symptom onset (P = 0.13), and duration of hospitalization (P = 0.04). Although further study is required, our findings provide a foundation for developing treatment strategies that factor in patients with specific disease phenotypes (which often require the use of aggressive hydration). These findings provide insights into underlying pathogenic mechanisms resulting in severe EVD and suggest direction for future research and development of effective treatment options.

Journal article

Martinón-Torres F, Png E, Khor CC, Davila S, Wright VJ, Sim KS, Vega A, Fachal L, Inwald D, Nadel S, Carrol ED, Martinón-Torres N, Alonso SM, Carracedo A, Morteruel E, López-Bayón J, Torre AC, Monge CC, de Aguilar PA, Torné EE, Martínez-Padilla MD, Martinón-Sánchez JM, Levin M, Hibberd ML, Salas A, ESIGEM network, ESPID meningococcal consortium UK, EUCLIDS consortium members - Imperial College London wwweuclids-projecteuet al., 2016, Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies, Scientific Reports, Vol: 6, ISSN: 2045-2322

Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10(-8)) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10(-9)). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10(-8)). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.

Journal article

Herberg JA, Kaforou M, Wright VJ, Shailes H, Eleftherohorinou H, Hoggart CJ, Cebey-López M, Carter MJ, Janes VA, Gormley S, Shimizu C, Tremoulet AH, Barendregt AM, Salas A, Kanegaye J, Pollard AJ, Faust SN, Patel S, Kuijpers T, Martinón-Torres F, Burns JC, Coin LJ, Levin Met al., 2016, Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children, Journal of the American Medical Association, Vol: 316, Pages: 835-845, ISSN: 0002-9955

IMPORTANCE: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. OBJECTIVE: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. DESIGN, SETTING, AND PARTICIPANTS: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets. EXPOSURES: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. MAIN OUTCOMES AND MEASURES: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group. RESULTS: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller

Journal article

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