Imperial College London

DrTomParks

Faculty of MedicineDepartment of Infectious Disease

Clinical Senior Lecturer in Infectious Disease
 
 
 
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t.parks

 
 
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Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

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60 results found

Wirth SH, Pulle J, Seo J, Ollberding NJ, Nakagaayi D, Sable C, Bowen AC, Parks T, Carapetis J, Okello E, Beaton A, Ndagire Eet al., 2024, Outcomes of rheumatic fever in Uganda: a prospective cohort study, The Lancet Global Health, Vol: 12, Pages: e500-e508, ISSN: 2214-109X

BACKGROUND: Rheumatic heart disease is the largest contributor to cardiac-related mortality in children worldwide. Outcomes in endemic settings after its antecedent illness, acute rheumatic fever, are not well understood. We aimed to describe 3-5 year mortality, acute rheumatic fever recurrence, changes in carditis, and correlates of mortality after acute rheumatic fever. METHODS: We conducted a prospective cohort study of Ugandan patients aged 4-23 years who were diagnosed with definite acute rheumatic fever using the modified 2015 Jones criteria from July 1, 2017, to March 31, 2020, enrolled at three rheumatic heart disease registry sites in Uganda (in Mbarara, Mulago, or Lira), and followed up for at least 1 year after diagnosis. Patients with congenital heart disease were excluded. Patients underwent annual review, most recently in August, 2022. We calculated rates of mortality and acute rheumatic fever recurrence, tabulated changes in carditis, performed Kaplan-Meier survival analyses, and used Cox regression models to identify correlates of mortality. FINDINGS: Data were collected between Sept 1 and Sept 30, 2022. Of 182 patients diagnosed with definite acute rheumatic fever, 156 patients were included in the analysis. Of these 156 patients (77 [49%] male and 79 (51%) female; data on ethnicity not collected), 25 (16%) died, 21 (13%) had a cardiac-related death, and 17 (11%) had recurrent acute rheumatic fever over a median of 4·3 (IQR 3·0-4·8) years. 16 (24%) of the 25 deaths occurred within 1 year. Among 131 (84%) of 156 survivors, one had carditis progression by echo. Moderate-to-severe carditis (hazard ratio 12·7 [95% CI 3·9-40·9]) and prolonged PR interval (hazard ratio 4·4 [95% CI 1·7-11·2]) at acute rheumatic fever diagnosis were associated with increased cardiac-related mortality. INTERPRETATION: These are the first contemporary data from sub-Saharan Africa on medium-term acute rheumatic fev

Journal article

Pulle J, Ndagire E, Atala J, Fall N, Okello E, Oyella LM, Rwebembera J, Sable C, Parks T, Sarnacki R, Nakitto M, de Loizaga SR, Wirth S, Carapetis J, Beaton Aet al., 2024, Specificity of the Modified Jones Criteria., Pediatrics, Vol: 153

Journal article

Schurz H, Naranbhai V, Yates TA, Gilchrist J, Parks T, Dodd PJ, Möller M, Hoal EG, Morris AP, Hill AVSet al., 2024, Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture, eLife, Vol: 12, ISSN: 2050-084X

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h2 = 26.3%, 95% CI 23.7–29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10-8) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10-9) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure.

Journal article

Healy J, Longbottom K, Kent A, Whittaker E, Parks Tet al., 2023, On the lookout for post-streptococcal complications in the UK, ARCHIVES OF DISEASE IN CHILDHOOD, ISSN: 0003-9888

Journal article

Parks T, Narube L, Perman ML, Sakumeni K, Fong J, Engelman D, Colquhoun S, Steer A, Kado Jet al., 2023, Population-based assessment of cardiovascular complications of rheumatic heart disease in Fiji: a record-linkage analysis, BMJ Open, Vol: 13, Pages: 1-10, ISSN: 2044-6055

Objective: To determine population-based rates of nonfatal complications of rheumatic heart disease (RHD).Design: Retrospective cohort study based on multiple sources of routine clinical and administrative data amalgamated by probabilistic record-linkage.Setting: Fiji, an upper-middle-income country, where most of the population has access to government-funded health care services.Participants: National cohort of 2,116 patients with clinically apparent RHD aged 5-69 years during 2008-2012.Primary and secondary outcome measures: The primary outcome was hospitalisation for any of heart failure, atrial fibrillation, ischaemic stroke and infective endocarditis. Secondary outcomes were first hospitalisation for each of the complications individually in the national cohort as well as in hospital (n=1300) and maternity (n=210) subsets. Information on outcomes was obtained from discharge diagnoses coded in the hospital patient information system. Population-based rates were obtained using relative survival methods with census data as the denominator.Results: Among 2,116 patients in the national cohort (median age, 23.3 years; 57.7% female), 546 (25.8%) were hospitalised for an RHD complication, a substantial proportion of all cardiovascular admissions in the country during this period in those aged 0–40 years (heart failure, 210/454, 46.2%; ischaemic stroke 31/134, 23.3%). Absolute numbers of RHD complications peaked during the third decade of life with higher population-based rates in women compared to men (incidence rate ratio 1.4, 95% CI 1.3–1.6, P<0.001). Hospitalisation for any RHD complication was associated with substantially increased risk of death (hazard ratio, 5.4, 95% CI, 3.4–8.8, P<0.001), especially after the onset of heart failure (hazard ratio, 6.6, 95% CI, 4.8–9.1, P<0.001).Conclusions: Our study defines the burden of RHD-attributable morbidity in the general population of Fiji, potentially reflecting the situation in low- a

Journal article

Hamilton F, Mentzer AJ, Parks T, Baillie JK, Smith GD, Ghazal P, Timpson NJet al., 2023, Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease, The American Journal of Human Genetics, Vol: 110, Pages: 691-702, ISSN: 0002-9297

ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease.

Journal article

Camille H, Tomas U, Romain B, Parks T, Sriskandan S, De Prost N, Chosidow Oet al., 2023, Necrotising soft tissue infections, The Lancet Infectious Diseases, Vol: 23, Pages: e81-e94, ISSN: 1473-3099

The incidence of necrotising soft tissue infections (NSTI) has increased during recent decades such that most physicians might see at least one case of these potentially life-threatening infections in their career. Despite advances in care, NSTI are still associated with high morbidity and mortality, underlining a need for continued education of the medical community. In particular, failure to suspect NSTI fueled by poor awareness of the disease promotes delays to first surgical debridement, amplifying disease severity and adverse outcomes. This review will focus on practical approaches to management of NSTI including prompt recognition, initiation of specific management, exploratory surgery, and aftercare. Increased alertness and awareness for NSTI should improve time to diagnosis and early referral to specialised centers, with consequent improvement in NSTI prognosis.

Journal article

Hamilton F, Mentzer A, Parks T, Baillie JK, Davey Smith G, Ghazal P, Timpson NJet al., 2022, Variation in<i>ERAP2</i>has opposing effects on severe respiratory infection and autoimmune disease

<jats:title>Introduction</jats:title><jats:p><jats:italic>ERAP2</jats:italic>is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to<jats:italic>Yersinia pestis</jats:italic>, have marked changes in population allele frequency of the common single nucleotide polymorphism (SNP) rs2549794. This SNP in strong linkage disequilibrium with a key splicing SNP in<jats:italic>ERAP2</jats:italic>(rs2248374) and this suggests that variation at<jats:italic>ERAP2</jats:italic>may be relevant for protection from infection. rs2549794 is also associated with Crohn’s disease and findings imply balancing selection between infection and autoimmune disease at this locus. There have been no large-scale prospective case-control studies of variation at<jats:italic>ERAP2</jats:italic>and infection.</jats:p><jats:sec><jats:title>Methods</jats:title><jats:p>This study aimed to explore the association between variation at<jats:italic>ERAP2</jats:italic>and a) infection, b) autoimmune disease, and c) parental longevity as a proxy for lifespan. Genome Wide Association Studies (GWAS) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374. Additionally,<jats:italic>cis</jats:italic>expression and protein quantitative trait loci (QTLs) for<jats:italic>ERAP2</jats:italic>were used in Mendelian randomisation analyses.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Across all cohorts, the T allele (minor allele frequency of 0.4-0.5) of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01-1.05; p = 0.014). Effect estimates were larger in

Other

Gilchrist J, Auckland K, Parks T, Mentzer A, Goldblatt L, Naranbhai V, Band G, Rockett K, Toure OB, Konata S, Sissoko S, Djimde AA, Theera MA, Doumbo OK, Sow S, Floyd S, Ponnighaus JM, Wandorff DK, Crampin AC, Fine PEM, Fairfax BP, Hill AVSet al., 2022, Genome-wide association study of leprosy in Malawi and Mali, PLoS Pathogens, Vol: 18, Pages: 1-27, ISSN: 1553-7366

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10−9; OR = 0.51 [95% CI0.40 − 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modernpopulations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

Journal article

Miller KM, Lamagni T, Cherian T, Cannon JW, Parks T, Adegbola RA, Pickering J, Barnett T, Engel ME, Manning L, Bowen AC, Carapetis JR, Moore HC, Barth DD, Kaslow DC, Van Beneden CAet al., 2022, Standardization of epidemiological surveillance of invasive Group A streptococcal infections, Open Forum Infectious Diseases, Vol: 9, Pages: S31-S40, ISSN: 2328-8957

Invasive group A streptococcal (Strep A) infections occur when Streptococcus pyogenes, also known as beta-hemolytic group A Streptococcus, invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections.This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications (confirmed or probable, if applicable) for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection.Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large (eg, state-wide) and well defined population.Participant eligibility, surveillance population, and additional surveillance components such as the use of International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented.

Journal article

Scheel A, Beaton A, Katzenellenbogen J, Parks T, Miller KM, Cherian T, Van Beneden CA, Cannon JW, Moore HC, Bowen AC, Carapetis JRet al., 2022, Standardization of epidemiological surveillance of acute rheumatic fever, Open Forum Infectious Diseases, Vol: 9, Pages: S41-S49, ISSN: 2328-8957

Acute rheumatic fever (ARF) is a multiorgan inflammatory disorder that results from the body’s autoimmune response to pharyngitis or a skin infection caused by Streptococcus pyogenes (Strep A). Acute rheumatic fever mainly affects those in low- and middle-income nations, as well as in indigenous populations in wealthy nations, where initial Strep A infections may go undetected. A single episode of ARF puts a person at increased risk of developing long-term cardiac damage known as rheumatic heart disease. We present case definitions for both definite and possible ARF, including initial and recurrent episodes, according to the 2015 Jones Criteria, and we discuss current tests available to aid in the diagnosis.We outline the considerations specific to ARF surveillance methodology, including discussion on where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare, administrative database review), participant eligibility, and the surveillance population. Additional considerations for ARF surveillance, including implications for secondary prophylaxis and follow-up, ARF registers, community engagement, and the impact of surveillance, are addressed. Finally, the core elements of case report forms for ARF, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed.

Journal article

Scheel A, Miller KM, Beaton A, Katzenellenbogen J, Parks T, Cherian T, Van Beneden CA, Cannon JW, Moore HC, Bowen AC, Carapetis JR, for the Strep A Vaccine Global Consortium SAVAC Burden of Disease Working Groupet al., 2022, Standardization of epidemiological surveillance of rheumatic heart disease, Open Forum Infectious Diseases, Vol: 9, Pages: S50-S56, ISSN: 2328-8957

Rheumatic heart disease (RHD) is a long-term sequela of acute rheumatic fever (ARF), which classically begins after an untreated or undertreated infection caused by Streptococcus pyogenes (Strep A). RHD develops after the heart valves are permanently damaged due to ARF. RHD remains a leading cause of morbidity and mortality in young adults in resource-limited and low- and middle-income countries. This article presents case definitions for latent, suspected, and clinical RHD for persons with and without a history of ARF, and details case classifications, including differentiating between definite or borderline according to the 2012 World Heart Federation echocardiographic diagnostic criteria. This article also covers considerations specific to RHD surveillance methodology, including discussions on echocardiographic screening, where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare), participant eligibility, and the surveillance population. Additional considerations for RHD surveillance, including implications for secondary prophylaxis and follow-up, RHD registers, community engagement, and the negative impact of surveillance, are addressed. Finally, the core elements of case report forms for RHD, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed.

Journal article

Ndagire E, Ollberding N, Sarnacki R, Meghna M, Pulle J, Atala J, Agaba C, Kansiime R, Bowen A, Longenecker CT, Oyella L, Rwebembera J, Okello E, Parks T, Zang H, Carapetis J, Sable C, Beaton AZet al., 2022, Modelling study of the ability to diagnose acute rheumatic fever at different levels of the Ugandan healthcare system., BMJ Open, Vol: 12, Pages: e050478-e050478, ISSN: 2044-6055

OBJECTIVE: To determine the ability to accurately diagnose acute rheumatic fever (ARF) given the resources available at three levels of the Ugandan healthcare system. METHODS: Using data obtained from a large epidemiological database on ARF conducted in three districts of Uganda, we selected variables that might positively or negatively predict rheumatic fever based on diagnostic capacity at three levels/tiers of the Ugandan healthcare system. Variables were put into three statistical models that were built sequentially. Multiple logistic regression was used to estimate ORs and 95% CI of predictors of ARF. Performance of the models was determined using Akaike information criterion, adjusted R2, concordance C statistic, Brier score and adequacy index. RESULTS: A model with clinical predictor variables available at a lower-level health centre (tier 1) predicted ARF with an optimism corrected area under the curve (AUC) (c-statistic) of 0.69. Adding tests available at the district level (tier 2, ECG, complete blood count and malaria testing) increased the AUC to 0.76. A model that additionally included diagnostic tests available at the national referral hospital (tier 3, echocardiography, anti-streptolysin O titres, erythrocyte sedimentation rate/C-reactive protein) had the best performance with an AUC of 0.91. CONCLUSIONS: Reducing the burden of rheumatic heart disease in low and middle-income countries requires overcoming challenges of ARF diagnosis. Ensuring that possible cases can be evaluated using electrocardiography and relatively simple blood tests will improve diagnostic accuracy somewhat, but access to echocardiography and tests to confirm recent streptococcal infection will have the greatest impact.

Journal article

Ioannidis AG, Blanco-Portillo J, Sandoval K, Hagelberg E, Barberena-Jonas C, Hill AVS, Rodriguez-Rodriguez JE, Fox K, Robson K, Haoa-Cardinali S, Quinto-Cortes CD, Miquel-Poblete JF, Auckland K, Parks T, Sofro ASM, avila-Arcos MC, Sockell A, Homburger JR, Eng C, Huntsman S, Burchard EG, Gignoux CR, Verdugo RA, Moraga M, Bustamante CD, Mentzer AJ, Moreno-Estrada Aet al., 2021, Paths and timings of the peopling of Polynesia inferred from genomic networks, NATURE, Vol: 597, Pages: 522-+, ISSN: 0028-0836

Journal article

Okello E, Ndagire E, Muhamed B, Sarnacki R, Murali M, Pulle J, Atala J, Bowen AC, DiFazio MP, Nakitto MG, Harik NS, Kansiime R, Longenecker CT, Lwabi P, Agaba C, Norton SA, Omara IO, Oyella LM, Parks T, Rwebembera J, Spurney CF, Stein E, Tochen L, Watkins D, Zimmerman M, Carapetis JR, Sable CA, Beaton Aet al., 2021, Incidence of acute rheumatic fever in northern and western Uganda: a prospective, population-based study, The Lancet Global Health, Vol: 9, Pages: E1423-E1430, ISSN: 2214-109X

BackgroundAcute rheumatic fever is infrequently diagnosed in sub-Saharan African countries despite the high prevalence of rheumatic heart disease. We aimed to determine the incidence of acute rheumatic fever in northern and western Uganda.MethodsFor our prospective epidemiological study, we established acute rheumatic fever clinics at two regional hospitals in the north (Lira district) and west (Mbarara district) of Uganda and instituted a comprehensive acute rheumatic fever health messaging campaign. Communities and health-care workers were encouraged to refer children aged 3–17 years, with suspected acute rheumatic fever, for a definitive diagnosis using the Jones Criteria. Children were referred if they presented with any of the following: (1) history of fever within the past 48 h in combination with any joint complaint, (2) suspicion of acute rheumatic carditis, or (3) suspicion of chorea. We excluded children with a confirmed alternative diagnosis. We estimated incidence rates among children aged 5–14 years and characterised clinical features of definite and possible acute rheumatic fever cases.FindingsData were collected between Jan 17, 2018, and Dec 30, 2018, in Lira district and between June 5, 2019, and Feb 28, 2020, in Mbarara district. Of 1075 children referred for evaluation, 410 (38%) met the inclusion criteria; of these, 90 (22%) had definite acute rheumatic fever, 82 (20·0%) had possible acute rheumatic fever, and 24 (6%) had rheumatic heart disease without evidence of acute rheumatic fever. Additionally, 108 (26%) children had confirmed alternative diagnoses and 106 (26%) had an unknown alternative diagnosis. We estimated the incidence of definite acute rheumatic fever among children aged 5–14 years as 25 cases (95% CI 13·7–30·3) per 100 000 person-years in Lira district (north) and 13 cases (7·1–21·0) per 100 000 person-years in Mbarara district (west).InterpretationTo th

Journal article

Machipisa T, Chong M, Muhamed B, Chishala C, Shaboodien G, Pandie S, de Vries J, Laing N, Joachim A, Daniels R, Ntsekhe M, Hugo-Hamman CT, Gitura B, Ogendo S, Lwabi P, Okello E, Damasceno A, Novela C, Mocumbi AO, Madeira G, Musuku J, Mtaja A, ElSayed A, Elhassan HHM, Bode-Thomas F, Okeahialam BN, Zuhlke LJ, Mulder N, Ramesar R, Lesosky M, Parks T, Cordell HJ, Keavney B, Engel ME, Pare Get al., 2021, Association of novel locus with rheumatic heart disease in Black African individuals findings from the RHDGen study, JAMA Cardiology, Vol: 6, Pages: 1000-1011, ISSN: 2380-6583

Importance Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD.Objective To identify common genetic loci associated with RHD susceptibility in Black African individuals.Design, Setting, and Participants This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021.Main Outcomes and Measures Genetic associations with RHD.Results This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10−8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10−3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic ar

Journal article

Rodriguez OL, Gibson WS, Parks T, Emery M, Powell J, Strahl M, Deikus G, Auckland K, Eichler EE, Marasco WA, Sebra R, Sharp AJ, Smith ML, Bashir A, Watson CTet al., 2020, A novel framework for characterizing genomic haplotype diversity in the human immunoglobulin heavy chain locus, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

An incomplete ascertainment of genetic variation within the highly polymorphic immunoglobulin heavy chain locus (IGH) has hindered our ability to define genetic factors that influence antibody-mediated processes. Due to locus complexity, standard high-throughput approaches have failed to accurately and comprehensively capture IGH polymorphism. As a result, the locus has only been fully characterized two times, severely limiting our knowledge of human IGH diversity. Here, we combine targeted long-read sequencing with a novel bioinformatics tool, IGenotyper, to fully characterize IGH variation in a haplotype-specific manner. We apply this approach to eight human samples, including a haploid cell line and two mother-father-child trios, and demonstrate the ability to generate high-quality assemblies (>98% complete and >99% accurate), genotypes, and gene annotations, identifying 2 novel structural variants and 15 novel IGH alleles. We show multiplexing allows for scaling of the approach without impacting data quality, and that our genotype call sets are more accurate than short-read (>35% increase in true positives and >97% decrease in false-positives) and array/imputation-based datasets. This framework establishes a desperately needed foundation for leveraging IG genomic data to study population-level variation in antibody-mediated immunity, critical for bettering our understanding of disease risk, and responses to vaccines and therapeutics.

Journal article

Okello E, Murali M, Rwebembera J, Atala J, Bowen AC, Harik N, Kaudha G, Kitooleko S, Longenecker C, Ndagire E, Omara IO, Oyella LM, Parks T, Pulle J, Sable C, Sarnacki R, Stein E, Zimmerman M, de Klerk N, Carapetis J, Beaton Aet al., 2020, Cross-sectional study of population-specific streptococcal antibody titres in Uganda, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 105, Pages: 825-829, ISSN: 0003-9888

Journal article

Okello E, Ndagire E, Atala J, Bowen AC, DiFazio MP, Harik NS, Longenecker CT, Lwabi P, Murali M, Norton SA, Omara IO, Oyella LM, Parks T, Pulle J, Rwebembera J, Sarnacki RJ, Spurney CF, Stein E, Tochen L, Watkins D, Zimmerman M, Carapetis JR, Sable C, Beaton Aet al., 2020, Active case finding for rheumatic fever in an endemic country, Journal of the American Heart Association, Vol: 9, ISSN: 2047-9980

Background:Despite the high burden of rheumatic heart disease in sub‐Saharan Africa, diagnosis with acute rheumatic fever (ARF) is exceedingly rare. Here, we report the results of the first prospective epidemiologic survey to diagnose and characterize ARF at the community level in Africa.Methods and Results:A cross‐sectional study was conducted in Lira, Uganda, to inform the design of a broader epidemiologic survey. Key messages were distributed in the community, and children aged 3 to 17 years were included if they had either (1) fever and joint pain, (2) suspicion of carditis, or (3) suspicion of chorea, with ARF diagnoses made by the 2015 Jones Criteria. Over 6 months, 201 children met criteria for participation, with a median age of 11 years (interquartile range, 6.5) and 103 (51%) female. At final diagnosis, 51 children (25%) had definite ARF, 11 (6%) had possible ARF, 2 (1%) had rheumatic heart disease without evidence of ARF, 78 (39%) had a known alternative diagnosis (10 influenza, 62 malaria, 2 sickle cell crises, 2 typhoid fever, 2 congenital heart disease), and 59 (30%) had an unknown alternative diagnosis.Conclusions:ARF persists within rheumatic heart disease–endemic communities in Africa, despite the low rates reported in the literature. Early data collection has enabled refinement of our study design to best capture the incidence of ARF and to answer important questions on community sensitization, healthcare worker and teacher education, and simplified diagnostics for low‐resource areas. This study also generated data to support further exploration of the relationship between malaria and ARF diagnosis in rheumatic heart disease/malaria‐endemic countries.

Journal article

Ioannidis AG, Blanco-Portillo J, Sandoval K, Hagelberg E, Francisco Miquel-Poblete J, Moreno-Mayar JV, Esteban Rodriguez-Rodriguez J, Quinto-Cortes CD, Auckland K, Parks T, Robson K, Hill AVS, Avila-Arcos MC, Sockell A, Homburger JR, Wojcik GL, Barnes KC, Herrera L, Berrios S, Acuna M, Llop E, Eng C, Huntsman S, Burchard EG, Gignoux CR, Cifuentes L, Verdugo RA, Moraga M, Mentzer AJ, Bustamante CD, Moreno-Estrada Aet al., 2020, Native American gene flow into Polynesia predating Easter Island settlement, Nature, Vol: 583, Pages: 572-577, ISSN: 0028-0836

The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas1,2,3,4,5,6, while critics have argued that these botanical dispersals need not have been human mediated7. The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui)2. Several limited molecular genetic studies have reached opposing conclusions, and the possibility continues to be as hotly contested today as it was when first suggested8,9,10,11,12. Here we analyse genome-wide variation in individuals from islands across Polynesia for signs of Native American admixture, analysing 807 individuals from 17 island populations and 15 Pacific coast Native American groups. We find conclusive evidence for prehistoric contact of Polynesian individuals with Native American individuals (around AD 1200) contemporaneous with the settlement of remote Oceania13,14,15. Our analyses suggest strongly that a single contact event occurred in eastern Polynesia, before the settlement of Rapa Nui, between Polynesian individuals and a Native American group most closely related to the indigenous inhabitants of present-day Colombia.

Journal article

Heenan RC, Parks T, Barnighausen T, Kado J, Bloom DE, Steer ACet al., 2020, The cost-of-illness due to rheumatic heart disease: national estimates for Fiji, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 114, Pages: 483-491, ISSN: 0035-9203

BackgroundRheumatic heart disease (RHD) is a chronic valvular heart disease that is responsible for a heavy burden of premature mortality in low- and middle-income countries. The total costs of RHD are important to health policy and research investment decisions. We estimate for the first time the total cost of RHD for Fiji (2008–2012) using a cost-of-illness approach and novel primary data on RHD disease burden and costs.MethodsRHD cases were identified using probabilistic record linkage across four routine data sources: (1) the Fiji RHD Control Program, (2) national hospital admissions records, (3) the Ministry of Health database of cause-specific deaths and (4) hospital ECG clinic registers. For each individual with RHD, we obtained information on RHD hospital admissions, treatment and death. We conducted a prevalence-based cost-of-illness analysis, including bottom-up assessment of indirect and direct (healthcare) costs.ResultsThe estimated cost of RHD in Fiji for 2008–2012 was year-2010 $FJ91.6 million (approximately US$47.7 million). Productivity losses from premature mortality constituted the majority of costs (71.4%). Indirect costs were 27-fold larger than the direct costs.ConclusionsRHD leads to a heavy economic burden in Fiji. Improved prevention strategies for RHD will likely confer substantial economic benefits to the country.

Journal article

Auckland K, Mittal B, Cairns BJ, Garg N, Kumar S, Mentzer AJ, Kado J, Perman ML, Steer AC, Hill AVS, Parks Tet al., 2020, The human leukocyte antigen locus and rheumatic heart disease susceptibility in South Asians and Europeans, Scientific Reports, Vol: 10, ISSN: 2045-2322

Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51–2.18, P = 3.48×10−10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.

Journal article

Muhamed B, Parks T, Sliwa K, 2020, Genetics of rheumatic fever and rheumatic heart disease, Nature Reviews Cardiology, Vol: 17, Pages: 145-154, ISSN: 1759-5002

Rheumatic heart disease (RHD) is a complication of group A streptococcal infection that results from a complex interaction between the genetic make-up of the host, the infection itself and several other environmental factors, largely reflecting poverty. RHD is estimated to affect 33.4 million people and results in 10.5 million disability-adjusted life-years lost globally. The disease has long been considered heritable but still little is known about the host genetic factors that increase or reduce the risk of developing RHD. In the 1980s and 1990s, several reports linked the disease to the human leukocyte antigen (HLA) locus on chromosome 6, followed in the 2000s by reports implicating additional candidate regions elsewhere in the genome. Subsequently, the search for susceptibility loci has been reinvigorated by the use of genome-wide association studies (GWAS) through which millions of variants can be tested for association in thousands of individuals. Early findings implicate not only HLA, particularly the HLA-DQA1 to HLA-DQB1 region, but also the immunoglobulin heavy chain locus, including the IGHV4-61 gene segment, on chromosome 14. In this Review, we assess the emerging role of GWAS in assessing RHD, outlining both the advantages and disadvantages of this approach. We also highlight the potential use of large-scale, publicly available data and the value of international collaboration to facilitate comprehensive studies that produce findings that have implications for clinical practice.

Journal article

Watkins D, Baker MG, Kumar RK, Parks Tet al., 2020, Epidemiology, Risk Factors, Burden and Cost of Acute Rheumatic Fever and Rheumatic Heart Disease, Acute Rheumatic Fever and Rheumatic Heart Disease, Pages: 1-18, ISBN: 9780323754606

This chapter reviews what is known about the health and economic “burden” of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) worldwide. Evidence on the epidemiology of RHD has grown substantially over the last decade, but much less is known about ARF. The majority of disease risk is conferred by environmental and social factors, including poor-quality housing and household crowding, poor nutrition, and low use of preventive health services. In 2016, RHD accounted for an estimated 300,000 deaths and 10 million disability-adjusted life-years (a summary measure of premature mortality and disability) globally, and an estimated 30 million people were living with the condition. Disease rates have declined around the world, with the residual burden of disease concentrated in low-income countries and in middle-income countries like India with large subnational health inequalities. RHD results in significant economic consequences for affected individuals and households, especially those requiring costly surgical care.

Book chapter

Parks T, Elliot K, Lamagni T, Auckland K, Mentzer AJ, Guy R, Cartledge D, Strakova L, O'Connor D, Pollard AJ, Neville MJ, Mahajan A, Ashrafian H, Chapman SJ, Hill AVS, Sriskandan S, Knight JCet al., 2020, Elevated risk of invasive group a streptococcal disease and host genetic variation in the human leukocyte antigen locus, Genes and Immunity, Vol: 21, Pages: 63-70, ISSN: 1466-4879

Invasive group A streptococcal (GAS) disease is uncommon but carries a high casefatality rate relative to other infectious diseases. Given the ubiquity of mild GASinfections, it remains unclear why healthy individuals will occasionally develop lifethreatening infections, raising the possibility of host genetic predisposition. Here, wepresent the results of a case-control study including 43 invasive GAS cases and1,540 controls. Using HLA imputation and linear mixed-models, we find each copy ofthe HLA-DQA1*01:03 allele associates with a two-fold increased risk of disease(odds ratio 2.3, 95% confidence interval 1.3-4.4, P=0.009), an association whichpersists with classical HLA typing of a subset of cases and analysis with analternative large control dataset with validated HLA data. Moreover, we propose theassociation is driven by the allele itself rather than the background haplotype. Overallthis finding provides impetus for further investigation of the immunogenetic basis ofthis devastating bacterial disease.

Journal article

Okello E, Ndagire E, Sarnacki R, Murali M, Rwebembera J, Parks T, de Klerk N, Longenecker C, Carapetis J, Sable CA, Beaton AZet al., 2019, Application of Population Specific Streptococcal Antibody Titers to Improve Specificity of Rheumatic Fever Diagnosis in Uganda, Scientific Sessions of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Parks T, Auckland K, Lamagni T, Mentzer A, Elliott K, Guy R, Cartledge D, Strakova L, OConnor D, Pollard A, Chapman S, Thomas M, Brodlie M, Colot J, DOrtenzio E, Baroux N, Mirabel M, Gilchrist J, Scott A, Williams T, Knight J, Steer A, Hill A, Sriskandan Set al., 2019, Host genetic variants near the <i>PAX5</i> gene locus associate with susceptibility to invasive group A streptococcal disease

We undertook a genome-wide association study of susceptibility to invasive group A streptococcal (GAS) disease combining data from distinct clinical manifestations and ancestral populations. Amongst other signals, we identified a susceptibility locus located 18kb from PAX5 , an essential B-cell gene, which conferred a nearly two-fold increased risk of disease (rs1176842, odds ratio 1.8, 95% confidence intervals 1.5-2.3, P=3.2×10 −7 ). While further studies are needed, this locus could plausibly explain some inter-individual differences in antibody-mediated immunity to GAS, perhaps providing insight into the effects of intravenous immunoglobulin in streptococcal toxic shock.

Other

Macleod CK, Bright P, Steer AC, Kim J, Mabey D, Parks Tet al., 2019, Neglecting the neglected: the objective evidence of underfunding in rheumatic heart disease, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 113, Pages: 287-290, ISSN: 0035-9203

BackgroundDespite the substantial global burden of disease, rheumatic heart disease research receives little funding globally.MethodsUsing data from the Global Burden of Disease Study and funding from the G-FINDER database, we propose a novel logarithmic disability neglect index (DNI) to describe disease burden using disability-adjusted life years relative to funding for 16 major tropical diseases.ResultsAcross a range of diseases, rheumatic heart disease received the least funding relative to disease burden (DNI=3.83). Other diseases facing similar underfunding include cysticercosis (DNI=2.71) and soil-transmitted helminths (DNI=2.41).ConclusionsRheumatic heart disease remains severely underfunded relative to disease burden.

Journal article

Parks T, Elliott K, Lamagni T, Auckland K, Mentzer A, Guy R, Cartledge D, Strakova L, OConnor D, Pollard A, Neville M, Mahajan A, Ashrafian H, Chapman S, Hill A, Sriskandan S, Knight Jet al., 2019, Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leukocyte antigen locus

Invasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1,540 controls. Using HLA imputation and linear mixed-models, we find each copy of the HLA-DQA1 *01:03 allele associates with a two-fold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4, P =0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.

Other

Parks T, Wilson C, Curtis N, Norrby-Teglund A, Sriskandan Set al., 2018, Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis., Clinical Infectious Diseases, Vol: 67, Pages: 1434-1436, ISSN: 1058-4838

We evaluated the effect of adjunctive intravenous immunoglobulin (IVIG) on mortality in clindamycin-treated streptococcal toxic shock syndrome patients using a meta-analysis. In association with IVIG, mortality fell from 33.7% to 15.7% (risk ratio 0.46, 95% confidence intervals 0.26-0.83, p=0.010) with remarkable consistency across the single randomised and four non-randomised studies.

Journal article

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