Using population-specific add-on polymorphisms to improve genotype imputation in underrepresented populations.

Genome-wide association studies rely on the statistical inference of untyped variants, called imputation, to increase the coverage of genotyping arrays. However, the results are often suboptimal in populations underrepresented in existing reference panels and array designs, since the selected single nucleotide polymorphisms (SNPs) may fail to capture population-specific haplotype structures, hence the full extent of common genetic variation. Here, we propose to sequence the full genomes of a small subset of an underrepresented study cohort to inform the selection of population-specific add-on tag SNPs and to generate an internal population-specific imputation reference panel, such that the remaining array-genotyped cohort could be more accurately imputed. Using a Tanzania-based cohort as a proof-of-concept, we demonstrate the validity of our approach by showing improvements in imputation accuracy after the addition of our designed add-on tags to the base H3Africa array.

Diagnostic delay and associated factors among patients with pulmonary tuberculosis in Dar es Salaam, Tanzania.

BACKGROUND: Tanzania is among the 30 countries with the highest tuberculosis (TB) burdens. Because TB has a long infectious period, early diagnosis is not only important for reducing transmission, but also for improving treatment outcomes. We assessed diagnostic delay and associated factors among infectious TB patients. METHODS: We interviewed new smear-positive adult pulmonary TB patients enrolled in an ongoing TB cohort study in Dar es Salaam, Tanzania, between November 2013 and June 2015. TB patients were interviewed to collect information on socio-demographics, socio-economic status, health-seeking behaviour, and residential geocodes. We categorized diagnostic delay into ≤ 3 or > 3 weeks. We used logistic regression models to identify risk factors for diagnostic delay, presented as crude (OR) and adjusted Odds Ratios (aOR). We also assessed association between geographical distance (incremental increase of 500 meters between household and the nearest pharmacy) with binary outcomes. RESULTS: We analysed 513 patients with a median age of 34 years (interquartile range 27-41); 353 (69%) were men. Overall, 444 (87%) reported seeking care from health care providers prior to TB diagnosis, of whom 211 (48%) sought care > 2 times. Only six (1%) visited traditional healers before TB diagnosis. Diagnostic delay was positively associated with absence of chest pain (aOR = 7.97, 95% confidence intervals [CI]: 3.15-20.19; P < 0.001), and presence of hemoptysis (aOR = 25.37, 95% CI: 11.15-57.74; P < 0.001) and negatively associated with use of medication prior to TB diagnosis (aOR = 0.31, 95% CI: 0.14-0.71; P = 0.01). Age, sex, HIV status, education level, household income, and visiting health care facilities (HCFs) were not associated with diagnostic delay. Patients living far from pharmacies were less likely to visit a HCF (incremental increase of distance versus visit to any facility: OR = 0.51, 95% CI: 0.28-0.96; P = 0.037). CONCLUSIONS: TB diagnostic delay was common in Dar es Salaam, and was more likely among patients without prior use of medication and presenting with hemoptysis. Geographical distance to HCFs may have an impact on health-seeking behaviour. Increasing community awareness of TB signs and symptoms could further reduce diagnostic delays and interrupt TB transmission.

Prevalence and clinical relevance of helminth co-infections among tuberculosis patients in urban Tanzania.

BACKGROUND: Helminth infections can negatively affect the immunologic host control, which may increase the risk of progression from latent Mycobacterium tuberculosis infection to tuberculosis (TB) disease and alter the clinical presentation of TB. We assessed the prevalence and determined the clinical relevance of helminth co-infection among TB patients and household contact controls in urban Tanzania. METHODOLOGY: Between November 2013 and October 2015, we enrolled adult (≥18 years) sputum smear-positive TB patients and household contact controls without TB during an ongoing TB cohort study in Dar es Salaam, Tanzania. We used Baermann, FLOTAC, Kato-Katz, point-of-care circulating cathodic antigen, and urine filtration to diagnose helminth infections. Multivariable logistic regression models with and without random effects for households were used to assess for associations between helminth infection and TB. PRINCIPAL FINDINGS: A total of 597 TB patients and 375 household contact controls were included. The median age was 33 years and 60.2% (585/972) were men. The prevalence of any helminth infection among TB patients was 31.8% (190/597) and 25.9% (97/375) among controls. Strongyloides stercoralis was the predominant helminth species (16.6%, 161), followed by hookworm (9.0%, 87) and Schistosoma mansoni (5.7%, 55). An infection with any helminth was not associated with TB (adjusted odds ratio (aOR) 1.26, 95% confidence interval (CI): 0.88-1.80, p = 0.22), but S. mansoni infection was (aOR 2.15, 95% CI: 1.03-4.45, p = 0.040). Moreover, S. mansoni infection was associated with lower sputum bacterial load (aOR 2.63, 95% CI: 1.38-5.26, p = 0.004) and tended to have fewer lung cavitations (aOR 0.41, 95% CI: 0.12-1.16, p = 0.088). CONCLUSIONS/SIGNIFICANCE: S. mansoni infection was an independent risk factor for active TB and altered the clinical presentation in TB patients. These findings suggest a role for schistosomiasis in modulating the pathogenesis of human TB. Treatment of helminths should be considered in clinical management of TB and TB control programs.

Home-Based and Facility-Based Directly Observed Therapy of Tuberculosis Treatment under Programmatic Conditions in Urban Tanzania.

INTRODUCTION: Decentralization of Directly Observed Treatment (DOT) for tuberculosis (TB) to the community (home-based DOT) has improved the coverage of TB treatment and reduced the burden to the health care facilities (facility-based DOT). We aimed to compare TB treatment outcomes in home-based and facility-based DOT under programmatic conditions in an urban setting with a high TB burden. METHODOLOGY: A retrospective analysis of a cohort of adult TB patients (≥15 years) routinely notified between 2010 and 2013 in two representative TB sub-districts in the Temeke district, Dar es Salaam, Tanzania. We assessed differences in treatment outcomes by calculating Risk Ratios (RRs). We used logistic regression to assess the association between DOT and treatment outcomes. RESULTS: Data of 4,835 adult TB patients were analyzed, with a median age of 35 years, 2,943 (60.9%) were men and TB/HIV co-infection prevalence of 39.9%. A total of 3,593 (74.3%) patients were treated under home-based DOT. Patients on home-based DOT were more likely to die compared to patients on facility-based DOT (RR 2.04, 95% Confidence Interval [95% CI]: 1.52-2.73), and more likely to complete TB treatment (RR 1.14, 95% CI: 1.06-1.23), but less likely to have a successful treatment outcome (RR 0.94, 95% CI: 0.92-0.97). Home-based DOT was preferred by women (adjusted Odds Ratio [aOR] 1.55, 95% CI: 1.34-1.80, p<0.001), older people (aOR 1.01 for each year increase, 95% CI: 1.00-1.02, p = 0.001) and patients with extra-pulmonary TB (aOR 1.45, 95% CI: 1.16-1.81, p = 0.001), but less frequently by patients on a retreatment regimen (aOR 0.12, 95% CI: 0.08-0.19, p<0.001). CONCLUSIONS/SIGNIFICANCE: TB patients under home-based DOT had more frequently risk factors of death such as older age, HIV infection and sputum smear-negative TB, and had higher mortality compared to patients under facility-based DOT. Further operational research is needed to monitor the implementation of DOT under programmatic conditions.