Rebecca Nsubuga
Makerere University, Mathematics, Department Member
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Research Interests: Demography, Incidence Geometry, Male Circumcision, Medical Microbiology, Adolescent, and 15 moreMedicine, Humans, Models, Computer Simulation, Female, Male, Psychological Intervention, Incidence, Clinical Sciences, Middle Aged, Adult, Public health systems and services research, Microbicide, Communicable disease control, and HIV infections
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S OF PLENARY PRESENTATIONS A3 ABSTRACTS OF ORAL PRESENTATIONS A5S OF ORAL PRESENTATIONS A5 ABSTRACTS OF POSTER PRESENTATIONS A16S OF POSTER PRESENTATIONS A16
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Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for... more
Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for 50 years, frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants in this population and the location of breakpoints along the genome. As part of the PANGEA-HIV consortium, 1,472 consensus genome sequences over 5 kb have been obtained from 1,857 samples collected by the MRC/UVRI & LSHTM Research unit in Uganda, 465 (31.6 per cent) of which were near full-length sequences (>8 kb). Using the subtyping tool SCUEAL, we find that of the near full-length dataset, 233 (50.1 per cent) genomes contained only one subtype, 30.8 per cent A1 (n = 143), 17.6 per cent D (n = 82), and 1.7 per cent C (n = 8), while 49.9 per cent (n = 232) contained more than one subtype (including A1/D (n = 164), A1/C (n = 13), C/D (...
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ObjectivesWe examined virological outcomes, patterns of acquired HIV drug resistance (ADR), correlates of virological failure (VF) and acquired drug resistance among fisherfolk on first-line ART.MethodsWe enrolled 1169 adults on ART for a... more
ObjectivesWe examined virological outcomes, patterns of acquired HIV drug resistance (ADR), correlates of virological failure (VF) and acquired drug resistance among fisherfolk on first-line ART.MethodsWe enrolled 1169 adults on ART for a median duration of 6, 12, 24, 36 and ≥48 months and used a pooled VL testing approach to identify VF (VL ≥1000 copies/mL). We performed genotyping among VF cases and determined correlates of VF and ADR by logistic regression.ResultsThe overall virological suppression rate was 91.7% and ADR was detected in 71/97 (73.2%) VF cases. The most prevalent mutations were M184V/I (53.6%) for NRTIs and K103N (39.2%) for NNRTIs. Thymidine analogue mutations were detected in 21.6% of VF cases while PI mutations were absent. A zidovudine-based ART regimen, duration on ART (≥24 months) and secondary/higher education level were significantly associated with VF. A nevirapine-based regimen [adjusted OR (aOR): 1.87; 95% CI: 0.03–0.54)] and VL ≥10000 copies/mL (aOR: 3...
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Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288... more
Genome-wide association studies (GWAS) for kidney function have uncovered hundreds of risk loci, primarily in populations of European ancestry. We conducted the first GWAS of estimated glomerular filtration rate (eGFR) in Africa in 3288 Ugandans and replicated the findings in 8224 African Americans. We identified two loci associated with eGFR at genome-wide significance (p<5×10−8). The most significantly associated variant (rs2433603, p=2.4×10−9) in GATM was distinct from previously reported signals. A second association signal mapping near HBB (rs141845179, p=3.0×10−8) was not significant after conditioning on a previously reported SNP (rs334) for eGFR. However, fine-mapping analyses highlighted rs141845179 to be the most likely causal variant at the HBB locus (posterior probability of 0.61). A trans-ethnic GRS of eGFR constructed from previously reported lead SNPs was not predictive into the Ugandan population, indicating that additional large-scale efforts in Africa are necess...
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Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of... more
Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene [solute carrier family 6 member A4 (SLC6A4)] and human tryptophan hydroxylase 2 gene (TPH2) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in SLC6A4 and TPH2.Hypothesis: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs.Methods: Polymorphisms in SLC6A4 (5-HTTLPR, rs25531, 5-HTTLPR-rs25531, and STin2 VNTR) and TPH2 (rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ chil...
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In this work, we formulated and analysed a deterministic model to study the HIV-HCV co-infection dynamics in presence of HIV therapy. The HCV chronic stage was split into two periods: the period before and the period after onset of... more
In this work, we formulated and analysed a deterministic model to study the HIV-HCV co-infection dynamics in presence of HIV therapy. The HCV chronic stage was split into two periods: the period before and the period after onset of cirrhosis. This was done because the HCV chronic stage of infection is long, asymptomatic and infectious. The effective reproduction numbers, one of our outcome measures, were computed using the next generation matrix method. Numerical simulations were performed to support the analytical results from the model. The different parameters in the model were subjected to a sensitivity analysis to determine their relative importance on the HIV-HCV co-infection dynamics. The results indicated that both HIV and HCV infections enhance each other; and in the long run, increasing the rates at which people are put on HIV treatment reduces the prevalence of HCV in the community; however, it increases the prevalence of HIV. Therefore, there should be increased safer se...
Research Interests: Medicine and Asymptomatic
Globally, it is estimated that of the 36.7 million people infected with human immunodeficiency virus (HIV), 6.3% are coinfected with hepatitis C virus (HCV). Coinfection with HIV reduces the chance of HCV spontaneous clearance. In this... more
Globally, it is estimated that of the 36.7 million people infected with human immunodeficiency virus (HIV), 6.3% are coinfected with hepatitis C virus (HCV). Coinfection with HIV reduces the chance of HCV spontaneous clearance. In this work, we formulated and analysed a deterministic model to study the HIV and HCV coinfection dynamics in absence of therapy. Due to chronic stage of HCV infection being long, asymptomatic, and infectious, our model formulation was based on the splitting of the chronic stage into the following: before onset of cirrhosis and its complications and after onset of cirrhosis. We computed the basic reproduction numbers using the next generation matrix method. We performed numerical simulations to support the analytical results. We carried out sensitivity analysis to determine the relative importance of the different parameters influencing the HIV-HCV coinfection dynamics. The findings reveal that, in the long run, there is a substantial number of individuals ...
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Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have... more
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subj...
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Although fishing communities (FCs) in Uganda are disproportionately affected by HIV-1 relative to the general population (GP), the transmission dynamics are not completely understood. We earlier found most HIV-1 transmissions to occur... more
Although fishing communities (FCs) in Uganda are disproportionately affected by HIV-1 relative to the general population (GP), the transmission dynamics are not completely understood. We earlier found most HIV-1 transmissions to occur within FCs of Lake Victoria. Here, we test the hypothesis that HIV-1 transmission in FCs is isolated from networks in the GP. We used phylogeography to reconstruct the geospatial viral migration patterns in 8 FCs and 2 GP cohorts and a Bayesian phylogenetic inference in BEAST v1.8.4 to analyse the temporal dynamics of HIV-1 transmission. Subtype A1 (pol region) was most prevalent in the FCs (115, 45.1%) and GP (177, 50.4%). More recent HIV transmission pairs from FCs were found at a genetic distance (GD) <1.5% than in the GP (Fisher’s exact test, p = 0.001). The mean time depth for pairs was shorter in FCs (5 months) than in the GP (4 years). Phylogeographic analysis showed strong support for viral migration from the GP to FCs without evidence of su...
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Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of... more
Globally, early initiation of antiretroviral therapy for HIV led to a reduction in the estimated mortality from cryptococcal meningitis (CCM) from 624,700 in 2009 to 181,100 in 2014. However, CCM remains one of the leading causes of mortality among HIV infected patients especially in sub-Saharan Africa where 75% of the deaths occur. Most of the studies evaluating mortality have reported short-term mortality (at or before 10 weeks of therapy). We determined mortality and associated factors among patients treated for CCM in the CryptoDex trial (ISRCTN59144167) in Uganda, and the effect of dexamethasone adjunctive therapy on mortality at two years. We conducted a retrospective cohort study between May 2017 and July 2017 to determine the long term survival (up to 2 years post-randomization) of all patients who had been enrolled into the CryptoDex trial in Uganda. The CryptoDex trial recruited between April 2013 and February 2015. We estimated mortality rates and determined factors affec...
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Background. Hypertension and dyslipidemia are independent risk factors for coronary heart disease and commonly coexist. Cardiovascular risk can be reliably predicted using lipid ratios such as the atherogenic index, a useful prognostic... more
Background. Hypertension and dyslipidemia are independent risk factors for coronary heart disease and commonly coexist. Cardiovascular risk can be reliably predicted using lipid ratios such as the atherogenic index, a useful prognostic parameter for guiding timely interventions.Objective. We assessed the cardiovascular risk profile based on the atherogenic index of residents within a rural Ugandan cohort.Methods. In 2011, a population based survey was conducted among 7507 participants. Sociodemographic characteristics, physical measurements (blood pressure, weight, height, and waist and hip circumference), and blood sampling for nonfasting lipid profile were collected for each participant. Atherogenic risk profile, defined as logarithm base ten of (triglyceride divided by high density lipoprotein cholesterol), was categorised as low risk (<0.1), intermediate risk (0.1–0.24), and high risk (>0.24).Results. Fifty-five percent of participants were female and the mean age was 49.9...
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Supporting results. (DOCX 4161Â kb)
In various areas of modern statistical applications such as in Environmetrics, Image Processing, Epidemiology, Biology, Astronomy, Industrial Mathematics, and many others, we encounter challenges of analyzing massive data sets which are... more
In various areas of modern statistical applications such as in Environmetrics, Image Processing, Epidemiology, Biology, Astronomy, Industrial Mathematics, and many others, we encounter challenges of analyzing massive data sets which are spatially observable, often presented as maps, and temporally correlated. The analysis of such data is usually performed with the goal to obtain both the spatial interpolation and the temporal prediction. In both cases, the data-generating process has to be fitted by an appropriate stochastic model which should have two main properties: (i) it should provide a good fit to the true underlying model; (ii) its structure could not be too complicated avoiding considerable estimation error that appears by fitting the model to real data. Consequently, achieving the reasonable trade-off between the model uncertainty and the parameter uncertainty is one of the most difficult questions of modern statistical theory.
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HIV drug resistance (HIVDR) is of increasing health concern, especially among key populations. We investigated the prevalence of virological suppression (VS), prevalence and correlates of HIVDR in HIV-infected women, enrolled in a... more
HIV drug resistance (HIVDR) is of increasing health concern, especially among key populations. We investigated the prevalence of virological suppression (VS), prevalence and correlates of HIVDR in HIV-infected women, enrolled in a high-risk cohort. We enrolled 267 women initiated on first-line antiretroviral therapy (ART) between 2015 and 2018. Participants' plasma samples were analysed for HIV RNA viral load (VL) and genotypic resistance testing was performed on those with VL non-suppression (defined as VL≥1,000 copies/mL). We used the Stanford HIVDR database-algorithm to assess HIVDR mutations and logistic regression to assess risk factors for VL non-suppression and HIVDR. We observed an overall VS prevalence of 76.0% (203/267) and detected respective ADR prevalence to NNRTIs and NRTIs of 81.3% (CI; 67.4-91.1) and 45.8% (CI; 31.4-60.8) among the 48 successfully genotyped VL non-suppressors. NNRTI mutations were observed in 81.3% (39/48) of the genotyped participants and 45.8% ...
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Phylogenetic inference is useful in characterising HIV transmission networks and assessing where prevention is likely to have the greatest impact. However, estimating parameters that influence the network structure is still scarce, but... more
Phylogenetic inference is useful in characterising HIV transmission networks and assessing where prevention is likely to have the greatest impact. However, estimating parameters that influence the network structure is still scarce, but important in evaluating determinants of HIV spread. We analyzed 2017 HIV pol sequences (728 Lake Victoria fisherfolk communities (FFCs), 592 female sex workers (FSWs) and 697 general population (GP)) to identify transmission networks on Maximum Likelihood (ML) phylogenetic trees and refined them using time-resolved phylogenies. Network generative models were fitted to the observed degree distributions and network parameters, and corrected Akaike Information Criteria and Bayesian Information Criteria values were estimated. 347 (17.2%) HIV sequences were linked on ML trees (maximum genetic distance ≤4.5%, ≥95% bootstrap support) and, of these, 303 (86.7%) that consisted of pure A1 (n = 168) and D (n = 135) subtypes were analyzed in BEAST v1.8.4. The maj...
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The General Population Cohort (GPC) in south-western Uganda has a low HIV-1 incidence rate (<1%). However, new infections continue to emerge. In this research, 3796 HIV-1 pol sequences (GPC: n = 1418, non-GPC sites: n = 1223, Central... more
The General Population Cohort (GPC) in south-western Uganda has a low HIV-1 incidence rate (<1%). However, new infections continue to emerge. In this research, 3796 HIV-1 pol sequences (GPC: n = 1418, non-GPC sites: n = 1223, Central Uganda: n = 1010 and Eastern Uganda: n = 145) generated between 2003–2015 were analysed using phylogenetic methods with demographic data to understand HIV-1 transmission in this cohort and inform the epidemic response. HIV-1 subtype A1 was the most prevalent strain in the GPC area (GPC and non-GPC sites) (39.8%), central (45.9%) and eastern (52.4%) Uganda. However, in the GPC alone, subtype D was the predominant subtype (39.1%). Of the 524 transmission clusters identified by Cluster Picker, all large clusters (≥5 individuals, n = 8) involved individuals from the GPC. In a multivariate analysis, clustering was strongly associated with being female (adjusted Odds Ratio, aOR = 1.28; 95% CI, 1.06–1.54), being >25 years (aOR = 1.52; 95% CI, 1.16–2.0) a...
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Model and data description. (DOCX 460Â kb)
Background Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the... more
Background Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5–11 years) and adolescents (aged 12–17 years). Results We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with T...
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Uganda changed its antiretroviral therapy guidelines in 2014, increasing the CD4 threshold for antiretroviral therapy initiation from 350 cells/μl to 500 cells/μl. We investigate what effect this change in policy is likely to have on HIV... more
Uganda changed its antiretroviral therapy guidelines in 2014, increasing the CD4 threshold for antiretroviral therapy initiation from 350 cells/μl to 500 cells/μl. We investigate what effect this change in policy is likely to have on HIV incidence, morbidity, and programme costs, and estimate the cost-effectiveness of the change over different time horizons. We used a complex individual-based model of HIV transmission and antiretroviral therapy scale-up in Uganda. 100 model fits were generated by fitting the model to 51 demographic, sexual behaviour, and epidemiological calibration targets, varying 96 input parameters, using history matching with model emulation. An additional 19 cost and disability weight parameters were varied during the analysis of the model results. For each model fit, the model was run to 2030, with and without the change in threshold to 500 cells/μl. The change in threshold led to a 9.7% (90% plausible range: 4.3%-15.0%) reduction in incidence in 2030, and ave...
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This report describes the identification of a genetically confirmed linked heterosexual human immunodeficiency virus (HIV) superinfection (HIV-SI) in a woman with chronic HIV infection who acquired a second strain of the virus from her... more
This report describes the identification of a genetically confirmed linked heterosexual human immunodeficiency virus (HIV) superinfection (HIV-SI) in a woman with chronic HIV infection who acquired a second strain of the virus from her husband. Serum neutralizing antibody (NAb) responses against their homologous and heterologous viruses, including the superinfecting strain, in the woman and her husband were examined before and after onset of HIV-SI. The woman displayed a moderately potent and broad anti-HIV NAb response prior to superinfection but did not possess NAb activity against the superinfecting strain. This case highlights the unique potential of linked HIV-SI studies to examine natural protection from HIV infection.
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UNAIDS calls for fewer than 500,000 new HIV infections/year by 2020, with treatment-as-prevention being a key part of their strategy for achieving the target. A better understanding of the contribution to transmission of people at... more
UNAIDS calls for fewer than 500,000 new HIV infections/year by 2020, with treatment-as-prevention being a key part of their strategy for achieving the target. A better understanding of the contribution to transmission of people at different stages of the care pathway can help focus intervention services at populations where they may have the greatest effect. We investigate this using Uganda as a case study. An individual-based HIV/ART model was fitted using history matching. 100 model fits were generated to account for uncertainties in sexual behaviour, HIV epidemiology, and ART coverage up to 2015 in Uganda. A number of different ART scale-up intervention scenarios were simulated between 2016 and 2030. The incidence and proportion of transmission over time from people with primary infection, post-primary ART-naïve infection, and people currently or previously on ART was calculated. In all scenarios, the proportion of transmission by ART-naïve people decreases, from 70% (61%-79%) in...
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Dataset and supporting documentation collected as part of the HIV combination prevention study, a cluster randomised trial investigating the feasibility of conducting HIV combination prevention interventions in fishing communities in... more
Dataset and supporting documentation collected as part of the HIV combination prevention study, a cluster randomised trial investigating the feasibility of conducting HIV combination prevention interventions in fishing communities in Uganda. The dataset contains participant-provided responses including condom use, HIV prevention practices, and intervention take-up.
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To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral... more
To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3,985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2,833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remaine...
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The linear mixed model (LMM) is now routinely used to estimate heritability. Unfortunately, as we demonstrate, LMM estimates of heritability can be inflated when using a standard model. To help reduce this inflation, we used a more... more
The linear mixed model (LMM) is now routinely used to estimate heritability. Unfortunately, as we demonstrate, LMM estimates of heritability can be inflated when using a standard model. To help reduce this inflation, we used a more general LMM with two random effects-one based on genomic variants and one based on easily measured spatial location as a proxy for environmental effects. We investigated this approach with simulated data and with data from a Uganda cohort of 4,778 individuals for 34 phenotypes including anthropometric indices, blood factors, glycemic control, blood pressure, lipid tests, and liver function tests. For the genomic random effect, we used identity-by-descent estimates from accurately phased genome-wide data. For the environmental random effect, we constructed a covariance matrix based on a Gaussian radial basis function. Across the simulated and Ugandan data, narrow-sense heritability estimates were lower using the more general model. Thus, our approach addre...
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Research Interests: Genetic Drift, Population Genetics, Biology, Population genetics (Biology), Adolescent, and 15 moreMedicine, Multidisciplinary, Greece, Population, Humans, Haplotypes, Social Isolation, Phenotype, Genotype, Genetic variation, Nature Communications, Blood cells, Cohort Studies, Cell Size, and Gene frequency
Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of these models depends in part on how... more
Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simula...