Dr Thomas Crellen

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Scientific Themes: Tropical Medicine & Global Health

I'm a postgraduate researcher working in the Bacterial Resistance Analysis Group in the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok, Thailand. My project focusses on determining risk factors for acquisition of drug resistant bacteria among neonates in a Cambodian hospital. The main organism in both carriage and blood stream infections was Klebsiella pneumoniae, we have sequenced over 300 isolates and aim to use the whole genome data to reconstruct transmission networks within the ward.

Prior to starting at MORU I worked as a field epidemiologist for Médecins Sans Frontières in the Central African Republic and the Democratic Republic of Congo.

My PhD was at Imperial College London and the Wellcome Trust Sanger Institute, focussing on the genomics and epidemiology of Schistosoma mansoni, a neglected tropical disease. 

A link to my publications: https://scholar.google.co.th/citations?user=Y_b9Ti8AAAAJ&hl=en

Name Department Institution Country
Professor Ben Cooper Tropical Medicine Oxford University, Bangkok Thailand
Professor Paul Turner Tropical Medicine Oxford University, Siem Reap Cambodia
Dr Patrick Musicha Tropical Medicine Oxford University, Bangkok Thailand
Crellen T, Rao B, Piening T, Zeydner J, Siddiqui R. 2018. Seasonal upsurge of pneumococcal meningitis in the Central African Republic | Show Abstract | Read more

A high incidence of bacterial meningitis was observed in the Central African Republic (CAR) from December 2015 to May 2017 in three hospitals in the northwest of the country that are within the African meningitis belt. The majority of cases were caused by Streptococcus pneumoniae (249/328; 75.9%), which occurred disproportionately during the dry season (November-April) with a high case-fatality ratio of 41.6% (95% confidence interval [CI] 33.0, 50.8%). High rates of bacterial meningitis during the dry season in the meningitis belt are typically caused by Neisseria meningitidis (meningococcal meningitis), and our observations suggest that the risk of contracting S. pneumoniae (pneumococcal) meningitis is increased by the same environmental factors. Cases of meningococcal meningitis (67/328; 20.4%) observed over the same period were predominantly type W and had a lower case fatality rate of 9.6% (95% CI 3.6, 21.8%). Due to conflict and difficulties in accessing medical facilities, it is likely that the reported cases represented only a small proportion of the overall burden and that there is high underlying prevalence of S. pneumoniae carriage in the community. Nationwide vaccination campaigns in the CAR against meningitis have been limited to the use of MenAfriVac, which targets only meningococcal meningitis type A. We therefore highlight the need for expanded vaccine coverage to prevent additional causes of seasonal outbreaks.

Crellen T, Turner P, Pol S, Baker S, Nguyen TNT, Stoesser N, Day NPJ, Cooper B. 2018. Transmission dynamics and between-species interactions of multidrug-resistant Enterobacteriaceae | Show Abstract | Read more

Abstract Widespread resistance to antibiotics is among the gravest threats to modern medicine, and controlling the spread of multi-drug resistant Enterobacteriaceae has been given priority status by the World Health Organization. Interventions to reduce transmission within hospital wards may be informed by modifiable patient-level risk factors for becoming colonised, however understanding of factors that influence a patient’s risk of acquisition is limited. We analyse data from a one year prospective carriage study in a neonatal intensive care unit in Cambodia using Bayesian hierarchical models to estimate the daily probability of acquiring multi-drug resistant organisms, while accounting for patient-level time-varying covariates, including interactions between species, and interval-censoring of transmission events. We estimate the baseline daily probability for becoming colonised with third generation cephalosporin resistant (3GC-R) Klebsiella pneumoniae as 0.142 (95% credible interval [CrI] 0.066, 0.27), nearly ten times higher than the daily probability of acquiring 3GC-R Escherichia coli (0.016 [95% CrI 0.0038, 0.049]). Prior colonization with 3GC-R K. pneumoniae was associated with a greatly increased risk of a patient acquiring 3GC-R E. coli (odds ratio [OR] 6.4 [95% CrI 2.8, 20.9]). Breast feeding was associated with a reduced risk of colonization with both 3GC-R K. pneumoniae (OR 0.73 [95% CrI 0.38, 1.5]) and E. coli (OR 0.62 [95% CrI 0.28, 1.6]). The use of an oral probiotic ( Lactobacillus acidophilus ) did not show clear evidence of protection against colonization with either 3GC-R K. pneumoniae (OR 0.83 [95% CrI 0.51, 1.3]) or 3GC-R E. coli (OR 1.3 [95% CrI 0.77, 2.1]). Antibiotic consumption within the past 48 hours did not strongly influence the risk of acquiring 3GC-R K. pneumoniae . For 3GC-R E. coli , ceftriaxone showed the strongest effect for increasing the risk of acquisition (OR 2.2 [95% CrI 0.66, 6.2]) and imipenem was associated with a decreased risk (OR 0.31 [95% CrI 0.099, 0.76). Using 317 whole-genome assemblies of K. pneumoniae , we determined putatively related clusters and used a range of models to infer transmission rates. Model comparison strongly favored models with a time-varying force of infection term that increased in proportion with the number of colonized patients, providing evidence of patient-to-patient transmission, including among a cluster of Klebsiella quasipneumoniae . Our findings provide support for the hypothesis that K. pneumoniae can be spread person-to-person within ward settings. Subsequent horizontal gene transfer within patients from K. pneumoniae provides the most parsimonious explanation for the strong association between colonization with 3GC-R K. pneumoniae and acquisition of 3GC-R E. coli .

Crellen T, Ssonko C, Piening T, Simaleko MM, St. Calvaire DH, Gieger K, Siddiqui R. 2018. What drives mortality among HIV patients in a conflict setting? A prospective cohort study in the Central African Republic | Show Abstract | Read more

Background: Provision of antiretroviral therapy (ART) during conflict settings is rarely attempted and little is known about the expected patterns of mortality. The Central African Republic (CAR) continues to have a low coverage of ART despite an estimated 120,000 people living with HIV and 11,000 AIDS-related deaths in 2013. We present results from a cohort in Zemio, Haut-Mboumou prefecture. This region had the highest prevalence of HIV nationally (14.8% in 2010) and was subject to repeated attacks by armed groups on civilians during the observed period. Methods: Conflict from armed groups can impact cohort mortality rates i) directly if HIV patients are victims of armed conflict, or ii) indirectly if population displacement or fear of movement reduces access to ART. Using monthly counts of civilian deaths, injuries and abductions, we estimated the impact of the conflict on patient mortality. We also determine patient-level risk factors for mortality and how this varies with time spent in the cohort. Model-fitting was performed in a Bayesian framework, using generalised-linear models with terms accounting for temporal autocorrelation. Results: Patients were recruited and observed from October 2011 to May 2017. Overall 1631 patients were enrolled, giving 4107 person-years and 148 deaths. Our first model shows that patient mortality did not increase during periods of heightened conflict. The monthly risk (probability) of mortality was markedly higher at the beginning of the program (0.047 in November 2011 [95% credible interval; CrI 0.0078, 0.21]) and had declined greater than ten-fold by the end of the observed period (0.0016 in June 2017 [95% CrI 0.00042, 0.0036]). Our second model shows the risk of mortality for individual patients was highest in the first five months spent in the cohort. Male sex was associated with a higher mortality (odds ratio; OR 1.7 [95% CrI 1.2, 2.8]) along with the severity of opportunistic infections at baseline. Conclusions: Our results show that chronic conflict did not appear to adversely affect rates of mortality in this cohort, and that mortality was driven predominantly by patient specific risk factors. In areas initiating ART for the first time, particular attention should be focussed on stabilising patients with advanced symptoms.

Nagraj VP, Randhawa N, Campbell F, Crellen T, Sudre B, Jombart T. 2018. epicontacts: Handling, visualisation and analysis of epidemiological contacts F1000Research, 7 | Show Abstract | Read more

Epidemiological outbreak data is often captured in line list and contact format to facilitate contact tracing for outbreak control. epicontacts is an R package that provides a unique data structure for combining these data into a single object in order to facilitate more efficient visualisation and analysis. The package incorporates interactive visualisation functionality as well as network analysis techniques. Originally developed as part of the Hackout3 event, it is now developed, maintained and featured as part of the R Epidemics Consortium (RECON). The package is available for download from the Comprehensive R Archive Network (CRAN) and GitHub .

Otto TD, Gilabert A, Crellen T, Böhme U, Arnathau C, Sanders M, Oyola SO, Okouga AP, Boundenga L, Willaume E et al. 2018. Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria. Nat Microbiol, 3 (6), pp. 687-697. | Show Abstract | Read more

Plasmodium falciparum, the most virulent agent of human malaria, shares a recent common ancestor with the gorilla parasite Plasmodium praefalciparum. Little is known about the other gorilla- and chimpanzee-infecting species in the same (Laverania) subgenus as P. falciparum, but none of them are capable of establishing repeated infection and transmission in humans. To elucidate underlying mechanisms and the evolutionary history of this subgenus, we have generated multiple genomes from all known Laverania species. The completeness of our dataset allows us to conclude that interspecific gene transfers, as well as convergent evolution, were important in the evolution of these species. Striking copy number and structural variations were observed within gene families and one, stevor, shows a host-specific sequence pattern. The complete genome sequence of the closest ancestor of P. falciparum enables us to estimate the timing of the beginning of speciation to be 40,000-60,000 years ago followed by a population bottleneck around 4,000-6,000 years ago. Our data allow us also to search in detail for the features of P. falciparum that made it the only member of the Laverania able to infect and spread in humans.

Nagraj VP, Randhawa N, Campbell F, Crellen T, Sudre B, Jombart T. 2018. epicontacts: Handling, visualisation and analysis of epidemiological contacts F1000Research, 7 pp. 566-566. | Show Abstract | Read more

Epidemiological outbreak data is often captured in line list and contact format to facilitate contact tracing for outbreak control. epicontacts is an R package that provides a unique data structure for combining these data into a single object in order to facilitate more efficient visualisation and analysis. The package incorporates interactive visualisation functionality as well as network analysis techniques. Originally developed as part of the Hackout3 event, it is now developed, maintained and featured as part of the R Epidemics Consortium (RECON). The package is available for download from the Comprehensive R Archive Network (CRAN) and GitHub .

Crellen T, Rao VB, Piening T, Zeydner J, Siddiqui MR. 2018. Seasonal upsurge of pneumococcal meningitis in the Central African Republic. Wellcome Open Res, 3 pp. 134. | Show Abstract | Read more

A high incidence of bacterial meningitis was observed in the Central African Republic (CAR) from December 2015 to May 2017 in three hospitals in the northwest of the country that are within the African meningitis belt. The majority of cases were caused by Streptococcus pneumoniae (249/328; 75.9%), which occurred disproportionately during the dry season (November-April) with a high case-fatality ratio of 41.6% (95% confidence interval [CI] 33.0, 50.8%). High rates of bacterial meningitis during the dry season in the meningitis belt have typically been caused by Neisseria meningitidis (meningococcal meningitis), and our observations suggest that the risk of contracting S. pneumoniae (pneumococcal) meningitis is increased by the same environmental factors. Cases of meningococcal meningitis (67/328; 20.4%) observed over the same period were predominantly group W and had a lower case fatality rate of 9.6% (95% CI 3.6, 21.8%). Due to conflict and difficulties in accessing medical facilities, it is likely that the reported cases represented only a small proportion of the overall burden. Nationwide vaccination campaigns in the CAR against meningitis have been limited to the use of MenAfriVac, which targets only meningococcal meningitis group A. We therefore highlight the need for expanded vaccine coverage to prevent additional causes of seasonal outbreaks.

Nagraj VP, Randhawa N, Campbell F, Crellen T, Sudre B, Jombart T. 2018. epicontacts: Handling, visualisation and analysis of epidemiological contacts. F1000Res, 7 pp. 566. | Show Abstract | Read more

Epidemiological outbreak data is often captured in line list and contact format to facilitate contact tracing for outbreak control. epicontacts is an R package that provides a unique data structure for combining these data into a single object in order to facilitate more efficient visualisation and analysis. The package incorporates interactive visualisation functionality as well as network analysis techniques. Originally developed as part of the Hackout3 event, it is now developed, maintained and featured as part of the R Epidemics Consortium (RECON). The package is available for download from the Comprehensive R Archive Network (CRAN) and GitHub.

Crellen T, Walker M, Lamberton PHL, Kabatereine NB, Tukahebwa EM, Cotton JA, Webster JP. 2016. Reduced Efficacy of Praziquantel Against Schistosoma mansoni Is Associated With Multiple Rounds of Mass Drug Administration. Clin Infect Dis, 63 (9), pp. 1151-1159. | Show Abstract | Read more

BACKGROUND: Mass drug administration (MDA) with praziquantel is the cornerstone of schistosomiasis control in sub-Saharan Africa. The effectiveness of this strategy is dependent on the continued high efficacy of praziquantel; however, drug efficacy is rarely monitored using appropriate statistical approaches that can detect early signs of wane. METHODS: We conducted a repeated cross-sectional study, examining children infected with Schistosoma mansoni from 6 schools in Uganda that had previously received between 1 and 9 rounds of MDA with praziquantel. We collected up to 12 S. mansoni egg counts from 414 children aged 6-12 years before and 25-27 days after treatment with praziquantel. We estimated individual patient egg reduction rates (ERRs) using a statistical model to explore the influence of covariates, including the number of prior MDA rounds. RESULTS: The average ERR among children within schools that had received 8 or 9 previous rounds of MDA (95% Bayesian credible interval [BCI], 88.23%-93.64%) was statistically significantly lower than the average in schools that had received 5 rounds (95% BCI, 96.13%-99.08%) or 1 round (95% BCI, 95.51%-98.96%) of MDA. We estimate that 5.11%, 4.55%, and 16.42% of children from schools that had received 1, 5, and 8-9 rounds of MDA, respectively, had ERRs below the 90% threshold of optimal praziquantel efficacy set by the World Health Organization. CONCLUSIONS: The reduced efficacy of praziquantel in schools with a higher exposure to MDA may pose a threat to the effectiveness of schistosomiasis control programs. We call for the efficacy of anthelmintic drugs used in MDA to be closely monitored.

Crellen T, Allan F, David S, Durrant C, Huckvale T, Holroyd N, Emery AM, Rollinson D, Aanensen DM, Berriman M et al. 2016. Whole genome resequencing of the human parasite Schistosoma mansoni reveals population history and effects of selection. Sci Rep, 6 (1), pp. 20954. | Show Abstract | Read more

Schistosoma mansoni is a parasitic fluke that infects millions of people in the developing world. This study presents the first application of population genomics to S. mansoni based on high-coverage resequencing data from 10 global isolates and an isolate of the closely-related Schistosoma rodhaini, which infects rodents. Using population genetic tests, we document genes under directional and balancing selection in S. mansoni that may facilitate adaptation to the human host. Coalescence modeling reveals the speciation of S. mansoni and S. rodhaini as 107.5-147.6KYA, a period which overlaps with the earliest archaeological evidence for fishing in Africa. Our results indicate that S. mansoni originated in East Africa and experienced a decline in effective population size 20-90KYA, before dispersing across the continent during the Holocene. In addition, we find strong evidence that S. mansoni migrated to the New World with the 16-19th Century Atlantic Slave Trade.

Crellen T, Iantorno S. 2015. A switch in time. Nat Rev Microbiol, 13 (4), pp. 190. | Read more

Lamberton PHL, Crellen T, Cotton JA, Webster JP. 2015. Modelling the effects of mass drug administration on the molecular epidemiology of schistosomes. Adv Parasitol, 87 pp. 293-327. | Show Abstract | Read more

As national governments scale up mass drug administration (MDA) programs aimed to combat neglected tropical diseases (NTDs), novel selection pressures on these parasites increase. To understand how parasite populations are affected by MDA and how to maximize the success of control programmes, it is imperative for epidemiological, molecular and mathematical modelling approaches to be combined. Modelling of parasite population genetic and genomic structure, particularly of the NTDs, has been limited through the availability of only a few molecular markers to date. The landscape of infectious disease research is being dramatically reshaped by next-generation sequencing technologies and our understanding of how repeated selective pressures are shaping parasite populations is radically altering. Genomics can provide high-resolution data on parasite population structure, and identify how loci may contribute to key phenotypes such as virulence and/or drug resistance. We discuss the incorporation of genetic and genomic data, focussing on the recently sequenced Schistosoma spp., into novel mathematical transmission models to inform our understanding of the impact of MDA and other control methods. We summarize what is known to date, the models that exist and how population genetics has given us an understanding of the effects of MDA on the parasites. We consider how genetic and genomic data have the potential to shape future research, highlighting key areas where data are lacking, and how future molecular epidemiology knowledge can aid understanding of transmission dynamics and the effects of MDA, ultimately informing public health policy makers of the best interventions for NTDs.

Cano J, Rebollo MP, Golding N, Pullan RL, Crellen T, Soler A, Kelly-Hope LA, Lindsay SW, Hay SI, Bockarie MJ, Brooker SJ. 2014. The global distribution and transmission limits of lymphatic filariasis: past and present. Parasit Vectors, 7 (1), pp. 466. | Show Abstract | Read more

BACKGROUND: Lymphatic filariasis (LF) is one of the neglected tropical diseases targeted for global elimination by 2020 and to guide elimination efforts countries have, in recent years, conducted extensive mapping surveys. Documenting the past and present distribution of LF and its environmental limits is important for a number of reasons. Here, we present an initiative to develop a global atlas of LF and present a new global map of the limits of LF transmission. METHODS: We undertook a systematic search and assembly of prevalence data worldwide and used a suite of environmental and climatic data and boosted regression trees (BRT) modelling to map the transmission limits of LF. RESULTS: Data were identified for 66 of the 72 countries currently endemic and for a further 17 countries where LF is no longer endemic. Our map highlights a restricted and highly heterogeneous distribution in sub-Saharan Africa, with transmission more widespread in West Africa compared to east, central and southern Africa where pockets of transmission occur. Contemporary transmission occurs across much of south and South-east Asia and the Pacific. Interestingly, the risk map reflects environmental conditions suitable for LF transmission across Central and South America, including the southern States of America, although active transmission is only known in a few isolated foci. In countries that have eliminated LF, our predictions of environmental suitability are consistent with historical distribution. CONCLUSIONS: The global distribution of LF is highly heterogeneous and geographically targeted and sustained control will be required to achieve elimination. This first global map can help evaluate the progress of interventions and guide surveillance activities.

Assefa LM, Crellen T, Kepha S, Kihara JH, Njenga SM, Pullan RL, Brooker SJ. 2014. Diagnostic accuracy and cost-effectiveness of alternative methods for detection of soil-transmitted helminths in a post-treatment setting in western Kenya. PLoS Negl Trop Dis, 8 (5), pp. e2843. | Show Abstract | Read more

OBJECTIVES: This study evaluates the diagnostic accuracy and cost-effectiveness of the Kato-Katz and Mini-FLOTAC methods for detection of soil-transmitted helminths (STH) in a post-treatment setting in western Kenya. A cost analysis also explores the cost implications of collecting samples during school surveys when compared to household surveys. METHODS: Stool samples were collected from children (n = 652) attending 18 schools in Bungoma County and diagnosed by the Kato-Katz and Mini-FLOTAC coprological methods. Sensitivity and additional diagnostic performance measures were analyzed using Bayesian latent class modeling. Financial and economic costs were calculated for all survey and diagnostic activities, and cost per child tested, cost per case detected and cost per STH infection correctly classified were estimated. A sensitivity analysis was conducted to assess the impact of various survey parameters on cost estimates. RESULTS: Both diagnostic methods exhibited comparable sensitivity for detection of any STH species over single and consecutive day sampling: 52.0% for single day Kato-Katz; 49.1% for single-day Mini-FLOTAC; 76.9% for consecutive day Kato-Katz; and 74.1% for consecutive day Mini-FLOTAC. Diagnostic performance did not differ significantly between methods for the different STH species. Use of Kato-Katz with school-based sampling was the lowest cost scenario for cost per child tested ($10.14) and cost per case correctly classified ($12.84). Cost per case detected was lowest for Kato-Katz used in community-based sampling ($128.24). Sensitivity analysis revealed the cost of case detection for any STH decreased non-linearly as prevalence rates increased and was influenced by the number of samples collected. CONCLUSIONS: The Kato-Katz method was comparable in diagnostic sensitivity to the Mini-FLOTAC method, but afforded greater cost-effectiveness. Future work is required to evaluate the cost-effectiveness of STH surveillance in different settings.

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