Contact tracing and isoniazid preventive therapy for prevention of childhood tuberculosis in The Gambia

Background Tuberculosis is a major public health problem worldwide and is characterized by a high incidence in The Gambia. Children acquire infection primarily from adults in their households, and especially young children are at higher risk of progressing to disease and death. In The Gambia, childhood tuberculosis is poorly addressed in the routine national TB program activities; contact tracing and isoniazid preventive therapy (IPT) are not implemented. The burden of childhood TB is therefore poorly characterized and the operational challenges of implementing IPT are not well understood. Methods TB symptoms screening questionnaire and tuberculin skin testing were administered in the community to child contacts of adults recently diagnosed with TB. Those with TB suggestive symptoms and/or positive TST result were further evaluated in a dedicated clinic with physical examination, chest x ray, sputum induction and examination with smear, Xpert MTB/RIF and culture. Adherence to IPT was measured by pill count and IsoScreen test. Results Co-prevalent TB disease was detected in child contacts both within and outside immediate household of the adult index TB case. Altogether, 1.6% of all child contacts screened had co-prevalent TB disease. 42.2% of the co-prevalent TB cases were among asymptomatic but TST positive child contacts. A combination of Xpert and culture was positive in 32.3% of all children diagnosed with TB, an increase of 9.7 – 22.6% over the yields from microscopy, Xpert and culture alone as individual tests. 255/328 (77.7%) children completed each of six months of IPT with good adherence. Conclusions Contact tracing restricted to symptom screening and immediate households would have missed nearly half of all co-prevalent TB disease in child contacts in this setting. A combination of Xpert and mycobacterial culture had incremental benefit for the bacteriological confirmation of TB disease in actively traced child contacts. Uptake of, and adherence to, IPT were high among the eligible child contacts

Contact tracing and isoniazid preventive therapy for prevention of childhood tuberculosis in The Gambia

Background Tuberculosis is a major public health problem worldwide and is characterized by a high incidence in The Gambia. Children acquire infection primarily from adults in their households, and especially young children are at higher risk of progressing to disease and death. In The Gambia, childhood tuberculosis is poorly addressed in the routine national TB program activities; contact tracing and isoniazid preventive therapy (IPT) are not implemented. The burden of childhood TB is therefore poorly characterized and the operational challenges of implementing IPT are not well understood. Methods TB symptoms screening questionnaire and tuberculin skin testing were administered in the community to child contacts of adults recently diagnosed with TB. Those with TB suggestive symptoms and/or positive TST result were further evaluated in a dedicated clinic with physical examination, chest x ray, sputum induction and examination with smear, Xpert MTB/RIF and culture. Adherence to IPT was measured by pill count and IsoScreen test. Results Co-prevalent TB disease was detected in child contacts both within and outside immediate household of the adult index TB case. Altogether, 1.6% of all child contacts screened had co-prevalent TB disease. 42.2% of the co-prevalent TB cases were among asymptomatic but TST positive child contacts. A combination of Xpert and culture was positive in 32.3% of all children diagnosed with TB, an increase of 9.7 – 22.6% over the yields from microscopy, Xpert and culture alone as individual tests. 255/328 (77.7%) children completed each of six months of IPT with good adherence. Conclusions Contact tracing restricted to symptom screening and immediate households would have missed nearly half of all co-prevalent TB disease in child contacts in this setting. A combination of Xpert and mycobacterial culture had incremental benefit for the bacteriological confirmation of TB disease in actively traced child contacts. Uptake of, and adherence to, IPT were high among the eligible child contacts

Sparsity in partial least squares regression models

Data sets with multiple responses and multiple predictor variables are increasingly common. It is known that such data sets often exhibit near multicollinearity and the traditional ordinary least squares (OLS) regression method do not perform well in such a setting because the mean square error of the OLS regression coefficients will be large and prediction performance will be poor. This drawback of OLS is often handled by using well-known dimension reduction methods; the focus in this thesis is Partial Least Squares (PLS). The following contributions are made in the thesis: (a) Introduce relevant components (RC) models characterized by restrictions on the joint covariance matrix of the response and predictor variables, and show that the univariate (single-response) version of the RC model can be represented as a Krylov model. These representations will shed more light on the understanding of PLS. Also, PLS algorithms are reviewed and presented as estimators of the RC models. (b) Unify various multiple-response regression models under the framework of the RC models, and review some multiple-response PLS methods. In addition, simulation studies are carried out to compare the prediction performance of multivariate PLS (PLS2) methods. (c) Propose novel sparse multivariate PLS (SPLS2) methods for parameter estimation and variable selection, which offers more flexibility compared to known SPLS2 methods, and compare the novel methods against methods in the literature in terms of prediction performance and accuracy in variable selection. (d) Apply the PLS regression methods to a proteomics data set to predict the severity of systemic sclerosis and identify candidate markers. Furthermore, compare the PLS, SPLS and OLS methods with regard to predictive ability using the proteomics data

Modelling disease progression of Multiple Sclerosis in a South Wales cohort

Objectives: To model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis. Study Design and settings: Longitudinal EDSS scores (20,854 observations) were collected for 1787 relapse-onset MS patients at MS clinics in South Wales and modelled using a multilevel model (MLM). The MLM adjusted for baseline covariates (sex, age of onset, year of diagnosis, and disease modifying treatments (DMTs)), and included interactions between baseline covariates and time variables. Results: The optimal model was truncated at 30 years after disease onset and excluded EDSS recorded within 3 months of relapse. As expected, older age of onset was associated with faster disease progression at 15 years (effect size (ES): 0.75; CI: 0.63, 0.86; P: 2011) progressed more slowly than those diagnosed historically (<2006); (ES: -0.46; CI: -0.75, -0.16; P: 0.006) and (ES: -0.95; CI: -1.20, -0.70; P: <0.001), respectively. Conclusion: We present a novel model of MS outcomes, accounting for the nonlinear trajectory of MS and effects of baseline covariates, validating well-known risk factors (sex and age of onset) associated with disease progression. Also, patients diagnosed more recently progressed more slowly than those diagnosed historically

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

The ADAMS project - a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the United Kingdom

Purpose Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. Participants Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. Findings to date As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing–remitting MS, and 13.5% have secondary progressive MS. Future plans Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries

Impact of whole population pneumococcal vaccination on pneumococcal carriage in infants in the first 8 weeks of life; a randomised controlled trial in The Gambia

Abstract: Background: Pneumococcal diseases are responsible for over 1 million deaths every year and most of these are children in sub-Saharan Africa. The 7-valent pneumococcal conjugate vaccine (PCV7) has recently been introduced into child immunisation schedule in The Gambia. Early age at acquisition and high pneumococcal serotype diversity in The Gambia demand close monitoring after PCV7 introduction. Objective: To determine the impact of community vaccination with PCV7 on nasopharyngeal carriage of pneumococci in newborn infants up to the age of 8 weeks. Methods: Twenty one representative rural Gambian villages were randomly allocated to intervention and control groups. One dose of PCV7 was given to older children and adults, 2 doses for children aged 12 – 30 months and 3 doses for infants less than 12 months of age. In control villages, PCV7 was given to those aged 30 months and below and one dose of meningococcal group C conjugate vaccine (MnCC) was given to those >30 months of age. Babies born during the trial were recruited and nasopharyngeal swabs (NPS) collected as soon after delivery as possible and then weekly till end of 8 weeks. Transport and processing of NPS were by standard methods. Prevalence and rates of acquisition of any pneumococcus, vaccine serotypes (VT), vaccine associated serotypes (VAT), non-vaccine serotypes (NVT) and non-typeable pneumococci (NT) were studied. Kaplan-Meier failure functions were used to study time to first acquisition of pneumococci and acquisition rates were compared using Cox regression model adjusting for clustering at village level. Results: One hundred eighty nine and 155 infants were recruited in intervention and control villages respectively. Overall prevalence of carriage by the 8th week of life was 75% and 80% in intervention and control arms respectively. Sixty seven serotypes were isolated in the study. Prevalence of VT carriage was significantly lower in intervention villages compared to control (11.1% vs. 27.4%, p<.001). NVT carriage was higher in intervention villages (68.3% vs. 60.6%, p=0.141) and there were statistically significant differences in the carriage rates of individual NVT; 7F (2.5% vs. 1.1%, p=.016), 10A (3.9% vs. 2.3%, p=.026) and 15B (4% vs. 1.6%, p=.001) in intervention compared to control villages. VAT and NT carriage were similar in both arms. The risk of acquisition of VT was significantly lower in intervention compared to control villages (hazard ratio 0.37; 95%CI 0.22 – 0.6, p<.001). For the NVT, risk of acquisition was higher in intervention villages compared to controls but was not statistically significant (hazard ratio 1.26; 96CI 0.94 – 1.68, p=.12). There was a slight but non-significant increased risk of acquisition of NT in intervention compared to control villages (hazard ratio 1.13; 95%CI 0.61 – 2.09). VAT 6A carriage was significantly lower in intervention compared to control villages (1.8% vs. 4% respectively, p=.002) and VAT 19A carriage was higher in intervention villages compared to controls but this was not statistically significant (2.3% vs. 1.6% respectively, p=.205). The presence of children <5years of age was associated with an increased risk of acquisition of VAT (hazard ratio 1.07; 95%CI 1.03 – 1.12, P<.001). Conclusion: High immune pressure through community vaccination with PCV7 in The Gambia resulted in a significant ‘indirect’ reduction in the carriage of pneumococci of vaccine serotypes in infants in their first 8 weeks of life in these communities. This was associated with increased acquisition of pneumococci of non-vaccine serotypes. These findings support both the introduction of PCV7 into The Gambia and the need for ongoing active surveillance

Impact of whole population pneumococcal vaccination on pneumococcal carriage in infants in the first 8 weeks of life; a randomised controlled trial in The Gambia

Abstract: Background: Pneumococcal diseases are responsible for over 1 million deaths every year and most of these are children in sub-Saharan Africa. The 7-valent pneumococcal conjugate vaccine (PCV7) has recently been introduced into child immunisation schedule in The Gambia. Early age at acquisition and high pneumococcal serotype diversity in The Gambia demand close monitoring after PCV7 introduction. Objective: To determine the impact of community vaccination with PCV7 on nasopharyngeal carriage of pneumococci in newborn infants up to the age of 8 weeks. Methods: Twenty one representative rural Gambian villages were randomly allocated to intervention and control groups. One dose of PCV7 was given to older children and adults, 2 doses for children aged 12 – 30 months and 3 doses for infants less than 12 months of age. In control villages, PCV7 was given to those aged 30 months and below and one dose of meningococcal group C conjugate vaccine (MnCC) was given to those >30 months of age. Babies born during the trial were recruited and nasopharyngeal swabs (NPS) collected as soon after delivery as possible and then weekly till end of 8 weeks. Transport and processing of NPS were by standard methods. Prevalence and rates of acquisition of any pneumococcus, vaccine serotypes (VT), vaccine associated serotypes (VAT), non-vaccine serotypes (NVT) and non-typeable pneumococci (NT) were studied. Kaplan-Meier failure functions were used to study time to first acquisition of pneumococci and acquisition rates were compared using Cox regression model adjusting for clustering at village level. Results: One hundred eighty nine and 155 infants were recruited in intervention and control villages respectively. Overall prevalence of carriage by the 8th week of life was 75% and 80% in intervention and control arms respectively. Sixty seven serotypes were isolated in the study. Prevalence of VT carriage was significantly lower in intervention villages compared to control (11.1% vs. 27.4%, p<.001). NVT carriage was higher in intervention villages (68.3% vs. 60.6%, p=0.141) and there were statistically significant differences in the carriage rates of individual NVT; 7F (2.5% vs. 1.1%, p=.016), 10A (3.9% vs. 2.3%, p=.026) and 15B (4% vs. 1.6%, p=.001) in intervention compared to control villages. VAT and NT carriage were similar in both arms. The risk of acquisition of VT was significantly lower in intervention compared to control villages (hazard ratio 0.37; 95%CI 0.22 – 0.6, p<.001). For the NVT, risk of acquisition was higher in intervention villages compared to controls but was not statistically significant (hazard ratio 1.26; 96CI 0.94 – 1.68, p=.12). There was a slight but non-significant increased risk of acquisition of NT in intervention compared to control villages (hazard ratio 1.13; 95%CI 0.61 – 2.09). VAT 6A carriage was significantly lower in intervention compared to control villages (1.8% vs. 4% respectively, p=.002) and VAT 19A carriage was higher in intervention villages compared to controls but this was not statistically significant (2.3% vs. 1.6% respectively, p=.205). The presence of children <5years of age was associated with an increased risk of acquisition of VAT (hazard ratio 1.07; 95%CI 1.03 – 1.12, P<.001). Conclusion: High immune pressure through community vaccination with PCV7 in The Gambia resulted in a significant ‘indirect’ reduction in the carriage of pneumococci of vaccine serotypes in infants in their first 8 weeks of life in these communities. This was associated with increased acquisition of pneumococci of non-vaccine serotypes. These findings support both the introduction of PCV7 into The Gambia and the need for ongoing active surveillance

Relevance of multiple sclerosis severity genotype in predicting disease course: A real-world cohort

Objective Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome wide association studies recently found the first genome wide significant single nucleotide variant (SNV, rs10191329A) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management. Methods We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1455 MS patients. We used logistic regression, survival analysis and propensity score matching to predict relevant long-term clinical outcomes. Results We were unable to detect any association between rs10191329A and a range of clinically relevant outcomes (e.g. time to EDSS milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329A. However, we were able to replicate association of two suggestive SNVs (rs7289446G and rs868824C) with development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset. Interpretation Identification of rs10191329A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome wide association studies associated with disease progression in neurodegenerative disorders