Browsing by Author "Gumedze, Freedom"
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- ItemOpen AccessClinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry(BioMed Central Ltd, 2006) Mayosi, Bongani; Wiysonge, Charles; Ntsekhe, Mpiko; Volmink, Jimmy; Gumedze, Freedom; Maartens, Gary; Aje, Akinyemi; Thomas, Baby; Thomas, Kandathil; Awotedu, Abolade; Thembela, Bongani; Mntla, Phindile; Maritz, Frans; Blackett, Kathleen; Nkouonlack,BACKGROUND:The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.
- ItemOpen AccessDetection and down-weighting of outliers in non-normal data: theory and application(2014-08-15) Chatora,Tinashe Daniel; Gumedze, Freedom; Little, Francesca; Haines, Linda
- ItemOpen AccessDevelopment of a risk score for constrictive pericarditis using the Investigation of the Management of Pericarditis randomised clinical trial dataset(2022) Geffen, Hayli; Gumedze, Freedom; Ntsekhe, MpikoDespite the recent global decline of tuberculosis infections, constrictive pericarditis, one of the most serious consequences of tuberculous pericarditis, continues to be a major cause of morbidity and mortality in sub-Saharan Africa. Currently, while the risk of constrictive pericarditis in individuals with tuberculous pericarditis does not appear to be uniform, there is no defined risk score available to predict an individual's baseline risk of constrictive pericarditis. Therefore the main aim of this research was to employ supervised learning classification using the data from 1400 participants enrolled in the first Investigation of the Management of Pericarditis randomised clinical trial to derive a risk score for constrictive pericarditis. While various supervised learning classification methods, including tree-based algorithms, support vector machines and artificial neural networks, were compared to stratify individuals according to low, medium and high risk for constrictive pericarditis, the final risk score was developed using logistic regression. Significant associations were found between constrictive pericarditis and the following predictors: HIV, New York Heart Association functional class, cardiac tamponade and effusive-constrictive pericarditis. Although prednisolone treatment was associated with a reduced relative risk of constrictive pericarditis in high (risk ratio = 0.59; 95% CI = 0.378 – 0.925) and medium (risk ratio = 0.12; 95% CI = 0.016 – 0.971) risk individuals, prednisolone treatment did not seem to benefit the individuals predicted to be at low risk (risk ratio = 0.92; 95% CI = 0.084 - 10.047) for constrictive pericarditis. These results confirm that the baseline risk of developing constrictive pericarditis in individuals with suspected or confirmed tuberculous pericarditis is not uniform. Importantly, interventions such as adjunctive prednisolone should only be recommended for individuals suspected to be at either medium or high risk for constrictive pericarditis as they are the most likely to benefit while prednisolone treatment should potentially be avoided in treating individuals with tuberculous pericarditis that are suspected to be at low risk for constrictive pericarditis as they are the least likely to derive any benefit.
- ItemOpen AccessDiagnostics for joint models for longitudinal and survival data(2021) Singini, Isaac Luwinga; Gumedze, Freedom; Mwambi, HenryJoint models for longitudinal and survival data are a class of models that jointly analyse an outcome repeatedly observed over time such as a bio-marker and associated event times. These models are useful in two practical applications; firstly focusing on survival outcome whilst accounting for time varying covariates measured with error and secondly focusing on the longitudinal outcome while controlling for informative censoring. Interest on the estimation of these joint models has grown in the past two and half decades. However, minimal effort has been directed towards developing diagnostic assessment tools for these models. The available diagnostic tools have mainly been based on separate analysis of residuals for the longitudinal and survival sub-models which could be sub-optimal. In this thesis we make four contributions towards the body of knowledge. We first developed influence diagnostics for the shared parameter joint model for longitudinal and survival data based on Cook's statistics. We evaluated the performance of the diagnostics using simulation studies under different scenarios. We then illustrated these diagnostics using real data set from a multi-center clinical trial on TB pericarditis (IMPI). The second contribution was to implement a variance shift outlier model (VSOM) in the two-stage joint survival model. This was achieved by identifying outlying subjects in the longitudinal sub-model and down-weighting before the second stage of the joint model. The third contribution was to develop influence diagnostics for the multivariate joint model for longitudinal and survival data. In this setting we considered two longitudinal outcomes, square root CD4 cell count which was Gaussian in nature and antiretroviral therapy (ART) uptake which was binary. We achieved this by extending the univariate case i based on Cook's statistics for all parameters. The fourth contribution was to implement influence diagnostics in joint models for longitudinal and survival data with multiple failure types (competing risk). Using IMPI data set we considered two competing events in the joint model; death and constrictive pericarditis. Using simulation studies and IMPI dataset the developed diagnostics identified influential subjects as well as observations. The performance of the diagnostics was over 98% in simulation studies. We further conducted sensitivity analyses to check the impact of influential subjects and/or observations on parameter estimates by excluding them and re-fitting the joint model. We observed subtle differences, overall in the parameter estimates, which gives confidence that the initial inferences are credible and can be relied on. We illustrated case deletion diagnostics using the IMPI trial setting, these diagnostics can also be applied to clinical trials with similar settings. We therefore make a strong recommendation to analysts to conduct influence diagnostics in the joint model for longitudinal and survival data to ascertain the reliability of parameter estimates. We also recommend the implementation of VSOM in the longitudinal part of the two-stage joint model before the second stage.
- ItemOpen AccessHIV infection is associated with a lower incidence of constriction in presumed tuberculous pericarditis: a prospective observational study(Public Library of Science, 2008) Ntsekhe, Mpiko; Wiysonge, Charles S; Gumedze, Freedom; Maartens, Gary; Commerford, Patrick J; Volmink, Jimmy A; Mayosi, Bongani MBACKGROUND: Pericardial constriction is a serious complication of tuberculous pericardial effusion that occurs in up to a quarter of patients despite anti-tuberculosis chemotherapy. The impact of human immunodeficiency virus (HIV) infection on the incidence of constrictive pericarditis following tuberculous pericardial effusion is unknown. Methods and RESULTS: We conducted a prospective observational study to determine the association between HIV infection and the incidence of constrictive pericarditis among 185 patients (median age 33 years) with suspected tuberculous pericardial effusion. These patients were recruited consecutively between March and October 2004 on commencement of anti-tuberculosis treatment, from 15 hospitals in Cameroon, Nigeria and South Africa. Surviving patients (N = 119) were assessed for clinical evidence of constrictive pericarditis at 3 and 6 months of follow-up. Clinical features of HIV infection were present in 42 (35.2%) of the 119 patients at enrolment into the study. 66 of the 119 (56.9%) patients consented to HIV testing at enrolment. During the 6 months of follow-up, a clinical diagnosis of constrictive pericarditis was made in 13 of the 119 patients (10.9 %, 95% confidence interval [CI] 5.9-18%). Patients with clinical features of HIV infection appear less likely to develop constriction than those without (4.8% versus 14.3%; P = 0.08). None of the 33 HIV seropositive patients developed constriction, but 8 (24.2%, 95%CI 11.1-42.3%) of the 33 HIV seronegative patients did (P = 0.005). In a multivariate logistic regression model adjusting simultaneously for several baseline characteristics, only clinical signs of HIV infection were significantly associated with a lower risk of constriction (odd ratio 0.14, 95% CI 0.02-0.87, P = 0.035). CONCLUSIONS: These data suggest that HIV infection is associated with a lower incidence of pericardial constriction in patients with presumed tuberculous pericarditis.
- ItemOpen AccessMortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.(Health & Medical Publishing Group, 2008) Mayosi, Bongani M; Wiysonge, Charles Shey; Ntsekhe, Mpiko; Gumedze, Freedom; Volmink Jimmy A; Maartens, Gary; Aje, Akinyemi; Thomas, Baby M; Thomas, Kandathil M; Awotedu, Abolade A; Bongani, Thembela; Mntla, Phindile; Maritz, Frans; Blackett, Kathleen Ngu; Nkouonlack, Duquesne C; Burch, Vanessa C; Rebe, Kevin; Parrish, Andy; Sliwa, Karen; Vezi, Brian Z; Alam, Nowshad; Brown, Basil G; Gould, Trevor; Visser, Tim; Magula, Nombulelo P; Commerford, Patrick JTuberculous pericarditis is one of the most severe forms of extrapulmonary tuberculosis, causing death or disability in a substantial proportion of affected people.1,2 In Africa, the incidence of tuberculous pericarditis is rising as a result of the HIV epidemic.3 The effect of HIV infection on survival in patients with tuberculous pericarditis is unknown.2,4 Whereas some investigators have suggested that HIV-infected patients with tuberculous pericarditis have a similar outcome to non-infected cases,5 others have shown that there may be an increase in mortality in HIV associated with tuberculous pericarditis.2,6,7 We established a prospective observational study, the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry, to obtain current information on the diagnosis, management and outcome of patients with presumed tuberculous pericarditis living in sub-Saharan Africa, where the burden of HIV infection is the greatest in the world.4,8-10 In this paper, we report the mortality rate and its predictors during the 6 months of antituberculosis treatment among patients enrolled in the regist
- ItemOpen AccessPregnancy-associated heart failure: a comparison of clinical presentation and outcome between hypertensive heart failure of pregnancy and idiopathic peripartum cardiomyopathy(Public Library of Science, 2015) Ntusi, Ntobeko B A; Badri, Motasim; Gumedze, Freedom; Sliwa, Karen; Mayosi, Bongani MAIMS: There is controversy regarding the inclusion of patients with hypertension among cases of peripartum cardiomyopathy (PPCM), as the practice has contributed significantly to the discrepancy in reported characteristics of PPCM. We sought to determine whether hypertensive heart failure of pregnancy (HHFP) (i.e., peripartum cardiac failure associated with any form of hypertension) and PPCM have similar or different clinical features and outcome. Methods and RESULTS: We compared the time of onset of symptoms, clinical profile (including electrocardiographic [ECG] and echocardiographic features) and outcome of patients with HHFP (n = 53; age 29.6 ± 6.6 years) and PPCM (n = 30; age 31.5 ± 7.5 years). The onset of symptoms was postpartum in all PPCM patients, whereas it was antepartum in 85% of HHFP cases (p<0.001). PPCM was more significantly associated with the following features than HHFP (p<0.05): twin pregnancy, smoking, cardiomegaly with lower left ventricular ejection fraction on echocardiography, and longer QRS duration, QRS abnormalities, left atrial hypertrophy, left bundle branch block, T wave inversion and atrial fibrillation on ECG. By contrast, HHFP patients were significantly more likely (p<0.05) to have a family history of hypertension, hypertension and pre-eclampsia in a previous pregnancy, tachycardia at presentation on ECG, and left ventricular hypertrophy on echocardiography. Chronic heart failure, intra-cardiac thrombus and pulmonary hypertension were found significantly more commonly in PPCM than in HHFP (p<0.05). There were 5 deaths in the PPCM group compared to none among HHFP cases (p = 0.005) during follow-up. CONCLUSION: There are significant differences in the time of onset of heart failure, clinical, ECG and echocardiographic features, and outcome of HHFP compared to PPCM, indicating that the presence of hypertension in pregnancy-associated heart failure may not fit the case definition of idiopathic PPCM.
- ItemOpen AccessThe prevalence, determinants, natural history and impact of atrial fibrillation and atrial flutter in patients with tuberculosis pericarditis - insights from the IMPI trial(2016) Chishala, Chishala; Pandie, Shaheen; Gumedze, Freedom; Mayosi, Bongani MTuberculosis is the most common cause of pericarditis in Africa. The dual human immunodeficiency virus (HIV)-tuberculosis epidemics are major contributors to the burden of extra-pulmonary tuberculosis, including tuberculous pericarditis. Mortality rates remain unacceptably high. Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. It is associated with increased cardiovascular mortality and morbidity, as well as complications related to thromboembolic disease and haemodynamic instability. Similarly, atrial flutter (AFL) is a common macro-reentry arrhythmia, often associated with AF and its complications. While there is a recognized association between atrial fibrillation and / or atrial flutter (AF/AFL) and tuberculous pericarditis, there are limited data regarding the prevalence, determinants, natural history, and outcomes of AF/AFL in tuberculous pericarditis. Hypothesis: In patients with tuberculous pericarditis, AF/AFL is common, and when compared to tuberculous pericarditis patients that are in sinus rhythm, is associated with increased morbidity and mortality. Aims In participants with tuberculous pericarditis enrolled into the Investigation of the Management of Pericarditis (IMPI) trial, we intend to: 1. Estimate the prevalence of AF/AFL 2. Describe the natural history of AF/AFL 3. Identify clinical, biochemical and, echocardiographic predictors of AF/AFL 4. Determine the clinical impact of AF/AFL.
- ItemOpen AccessA random effects variance shift model for detecting and accommodating outliers in meta-analysis(BioMed Central Ltd, 2011) Gumedze, Freedom; Jackson, DanBACKGROUND:Meta-analysis typically involves combining the estimates from independent studies in order to estimate a parameter of interest across a population of studies. However, outliers often occur even under the random effects model. The presence of such outliers could substantially alter the conclusions in a meta-analysis. This paper proposes a methodology for identifying and, if desired, downweighting studies that do not appear representative of the population they are thought to represent under the random effects model. METHODS: An outlier is taken as an observation (study result) with an inflated random effect variance. We used the likelihood ratio test statistic as an objective measure for determining whether observations have inflated variance and are therefore considered outliers. A parametric bootstrap procedure was used to obtain the sampling distribution of the likelihood ratio test statistics and to account for multiple testing. Our methods were applied to three illustrative and contrasting meta-analytic data sets. RESULTS: For the three meta-analytic data sets our methods gave robust inferences when the identified outliers were downweighted. CONCLUSIONS: The proposed methodology provides a means to identify and, if desired, downweight outliers in meta-analysis. It does not eliminate them from the analysis however and we consider the proposed approach preferable to simply removing any or all apparently outlying results. We do not however propose that our methods in any way replace or diminish the standard random effects methodology that has proved so useful, rather they are helpful when used in conjunction with the random effects model.
- ItemOpen AccessStatistical model selection techniques for the cox proportional hazards model: a comparative study(2022) Njati, Jolando; Gumedze, FreedomThe advancement in data acquiring technology continues to see survival data sets with many covariates. This has posed a new challenge for researchers in identifying important covariates for inference and prediction for a time-to-event response variable. In this dissertation, common Cox proportional hazards model selection techniques and a random survival forest technique were compared using five performance criteria measures. These performance measures were concordance index, integrated area under the curve, and , and R2 . To carry out this exercise, a multicentre clinical trial data set was used. A simulation study was also implemented for this comparison. To develop a Cox proportional model, a training dataset of 75% of the observations was used and the model selection techniques were implemented to select covariates. Full Cox PH models containing all covariates were also incorporated for analysis for both the clinical trial data set and simulations. The clinical trial data set showed that the full model and forward selection technique performed better with the performance metrics employed, though they do not reduce the complexity of the model as much as the Lasso technique does. The simulation studies also showed that the full model performed better than the other techniques, with the Lasso technique overpenalising the model from the simulation with the smaller data set and many covariates. AIC and BIC were less effective in computation than the rest of the variable selection techniques, but effectively reduced model complexity than their counterparts for the simulations. The integrated area under the curve was the performance metric of choice for choosing the final model for analysis on the real data set. This performance metric gave more efficient outcomes unlike the other metrics on all selection techniques. This dissertation hence showed that variable selection techniques differ according to the study design of the research as well as the performance measure used. Hence, to have a good model, it is important to not use a model selection technique in isolation. There is therefore need for further research and publish techniques that work generally well for different study designs to make the process shorter for most researchers.
- ItemOpen AccessThe role and essence of pilot trials and subgroup analysis in cardiovascular research: the IMPI trial experience(2019) Isiguzo, Godsent Chichebem; Ntsekhe, Mpiko; Thabane, Lehana; Sliwa, Karen; Gumedze, FreedomBackground Randomised control trials (RCTs) are capital-intensive projects and demand substantial human and capital resources. Therefore, proper planning, precise research questions and adequate thoughts are required in areas such as acceptability of the intervention, participant recruitment, and selection of measurable outcomes. Ensuring all these are possible before delving into the main work can be forecasted through pilot trials. They help in determining the feasibility of the intended critical endpoints and ensure the applicability of the result findings. However, no matter how noble and vital the results are, improper reporting can make them unusable. The thesis brings to the fore the importance of pilot trials in low- and medium-income countries and how they can help make a case for more extensive definitive trials. It then focuses on how subgroup analysis can be used as an essential statistical tool for fully understanding clinical trial results and can be used to unearth non-apparent results in RCT. In the thesis, we highlight the need for accurate, systematic and complete reporting of pilot trials, by critically appraising the literature on abstract reporting in heart failure. The thesis discusses several aspects of pilot trial processes to understand better its unique role in helping refine the components of RCT, to make the running smooth and findings affirmative. Leveraging on the experience of working as a clinical research fellow in the second Investigation for Management of Pericarditis in Africa (IMPI-2) trial, the lessons learnt in planning, designing, implementation, recruitment and reporting of the IMPI-2 pilot forms the nucleus of this thesis. The experience acquired in the process and how they can help in planning future definitive studies are discussed in different sections of the thesis. Methodology The thesis uses the experience gained in critical appraisal of the literature, participation in preliminary planning and active participation in a multicentre randomised control trial to understand the importance of some issues during an RCT. These areas include the need for specific objective setting, identification of research participants and collaborators, the acceptability of research intervention, proper identification of possible outcome measures, retention of participants and quality reporting of research findings. It begins with an overview of pilot trials, subgroup analysis and tuberculous pericarditis which is the primary disease focus of the IMPI project. Each subsequent chapter of the thesis is presented either as a published manuscript or prepared for submission as a manuscript. The quality of reporting of pilot trials is then examined by systematically surveying the reporting of abstracts of pilot trials in heart failure using the checklist of the Consolidated standard for reporting of trials (CONSORT) extension for pilot trials. A subgroup analysis of IMPI-1 trial planned a priori on the modification of the effect of prednisolone by baseline pericardiocentesis status of trial participants is used to highlight the role subgroup analysis can play in unmasking the group effect in the randomised control trial. The thesis then goes on to present the preliminary report of the IMPI-2 pilot study, highlighting the lessons learned and aspirations in need of refining. Retention of study participants is essential to achieve success in clinical trials, one way of ensuring this is by letting the study participants understand the objectives and processes of the research and gaining their confidence. Thus, in chapter six, we piloted the use of the University of California San Diego Brief Assessment of Capacity to Consent (UBACC), a screening tool for evaluation of informed consent (IC) comprehension as a training tool for iterative learning and evaluation of consent comprehension among IMPI-2 pilot trial participants. Results and Conclusion Enormous resources expended in clinical research can yield good returns before the main work commences, a well-planned micro trial run in the form of a pilot study is undertaken. Our systematic survey of abstracts of pilot trials in heart failure showed that reporting of abstracts of pilot trials is currently suboptimal. Deciding ahead of time on what to report by systematically identifying the different sections needed to inform the audience can improve the quality adequately. Planning subgroup analysis during the design of main studies can help reveal unsuspected findings. The subgroup analysis result showed that pericardiocentesis, despite its essential use among patients with pericardial effusion, did not significantly influence the effect of prednisolone on the primary critical outcomes among IMPI-1 participants. The preliminary report of IMPI-2 trial was designed as a two-phase study; phase 1 results showed that at 50mg, intrapericardial alteplase was safe in facilitating complete pericardiocentesis, while phase two showed that it was feasible to recruit, randomised and follow up patients in line with the study protocol. However, we identified participant retention as a considerable challenge. The result of the pilot revealed that more effort should be expended on participants’ education on the clinical condition, the reason for the trial and the need for follow-up adherence. There is also a need to make adequate provision for the use of field workers for contact tracing to reduce the dropout rate. In the main trial protocol, there may also be a need to reconsider the patient's selection and use of fibrinolysis in malignant effusion, judging from the high rate of 3 months mortality in this group of patients. The results of the informed consent study showed that an improved level of comprehension followed the use of iterative learning, a higher level of education and non-use of interpreters during informed consent delivery. These finding led us to conclude that every effort should be made to ensure that research participants entirely buy into the research they are asked to be part of through thorough information delivery. Doing so can help improve participants adherence to the trial follow-up.