Empirical Bayes Approach to Controlling Familywise Error: An Application to HIV Resistance Data

Statistical challenges arise in identifying meaningful patterns and structures from high dimensional genomic data sets. Relating HIV genotype (sequence of amino acids) to phenotypic resistance presents a typical problem. When the HIV virus is under antiretroviral drug pressure, unfavorable mutations of the target genes often lead to greatly increased resistance of the virus to drugs, including drugs the virus has not been exposed to. Identification of mutation combinations and their correlation to drug resistance is critical in guiding efficient prescription of HIV drugs. The identification of a subset of codons associated with drug resistance from a set of several hundreds of codons presents a multiple testing problem. Statistical issues arising from genomic data multiple testing procedures include the choice of the null test-statistic distribution used to define cut-offs. Controlling familywise error rate implies controlling the number of false positives among true nulls. Given the large number of hypotheses to be tested, the number of true nulls is unknown. We apply two multiple testing procedures (MTPs) controlling familywise error rate: an adhoc augmented-Bonferroni method and a Empirical Bayes procedure originally proposed in van der Laan, Birkner and Hubbard(2005). Using simulations, we demonstrate that the proposed MTPs are less conservative than the traditional methods such as Bonferroni and Holm\u27s procedures. We apply the methods to HIV resistance data where we wish to identify mutations in the protease gene associated with Amprenavir resistance

Efficacy Studies of Malaria Treatments in Africa: Efficient Estimation with Missing Indicators of Failure

Efficacy studies of malaria treatments can be plagued by indeterminate outcomes for some patients. The study motivating this paper defines the outcome of interest (treatment failure) as recrudescence and for some subjects, it is unclear whether a recurrence of malaria is due to that or new infection. This results in a specific kind of missing data. The effect of missing data in causal inference problems is widely recognized. Methods that adjust for possible bias from missing data include a variety of imputation procedures (extreme case analysis, hot-deck, single and multiple imputation), inverse weighting methods, and likelihood based methods (data augmentation, EM procedures and their extensions). In this article, we focus on multiple imputation, two inverse weighting procedures (the inverse probability of censoring weighted (IPCW) and the doubly robust (DR) estimators), and a likelihood based methodology (G-computation), comparing the methods\u27 applicability to the efficient estimation of malaria treatments effects. We present results from a simulation study as well as results from a data analysis of malaria efficacy studies from Uganda

Workshop report: building biostatistics capacity in Sub-saharan Africa-taking action

To address the need for capacity development in biostatistics in the Sub-Saharan African region and to move recommendations from previous workshops into action, we brought together biostatisticians from the region to provide an opportunity to brainstorm biostatistics capacity development in Africa, how to enhance what is being done and establish collaborative links to work together. In order to move key recommendations forward working groups were established to focus on the structure and content of a MSc Biostatistics and on the development of a concept paper for an Africa Centre for Biostatistics Excellence.Pan African Medical Journal 2015; 2

Analytical methods used in estimating the prevalence of HIV/AIDS from demographic and cross-sectional surveys with missing data: a systematic review.

BACKGROUND: Sero- prevalence studies often have a problem of missing data. Few studies report the proportion of missing data and even fewer describe the methods used to adjust the results for missing data. The objective of this review was to determine the analytical methods used for analysis in HIV surveys with missing data. METHODS: We searched for population, demographic and cross-sectional surveys of HIV published from January 2000 to April 2018 in Pub Med/Medline, Web of Science core collection, Latin American and Caribbean Sciences Literature, Africa-Wide Information and Scopus, and by reviewing references of included articles. All potential abstracts were imported into Covidence and abstracts screened by two independent reviewers using pre-specified criteria. Disagreements were resolved through discussion. A piloted data extraction tool was used to extract data and assess the risk of bias of the eligible studies. Data were analysed through a quantitative approach; variables were presented and summarised using figures and tables. RESULTS: A total of 3426 citations where identified, 194 duplicates removed, 3232 screened and 69 full articles were obtained. Twenty-four studies were included. The response rate for an HIV test of the included studies ranged from 32 to 96% with the major reason for the missing data being refusal to consent for an HIV test. Complete case analysis was the primary method of analysis used, multiple imputations 11(46%) was the most advanced method used, followed by the Heckman's selection model 9(38%). Single Imputation and Instrumental variables method were used in only two studies each, with 13(54%) other different methods used in several studies. Forty-two percent of the studies applied more than two methods in the analysis, with a maximum of 4 methods per study. Only 6(25%) studies conducted a sensitivity analysis, while 11(46%) studies had a significant change of estimates after adjusting for missing data. CONCLUSION: Missing data in survey studies is still a problem in disease estimation. Our review outlined a number of methods that can be used to adjust for missing data on HIV studies; however, more information and awareness are needed to allow informed choices on which method to be applied for the estimates to be more reliable and representative

Implementation of Point-of-Care Diagnostics Leads to Variable Uptake of Syphilis, Anemia and CD4+ T-Cell Count Testing in Rural Maternal and Child Health Clinics.

INTRODUCTION: Anemia, syphilis and HIV are high burden diseases among pregnant women in sub-Saharan Africa. A quasi-experimental study was conducted in four health facilities in Southern Mozambique to evaluate the effect of point-of-care technologies for hemoglobin quantification, syphilis testing and CD4+ T-cell enumeration performed within maternal and child health services on testing and treatment coverage, and assessing acceptability by health workers. METHODS: Demographic and testing data on women attending first antenatal care services were extracted from existing records, before (2011; n = 865) and after (2012; n = 808) introduction of point-of-care testing. Study outcomes per health facility were compared using z-tests (categorical variables) and Wilcoxon rank-sum test (continuous variables), while inverse variance weights were used to adjust for possible cluster effects in the pooled analysis. A structured acceptability-assessment interview was conducted with health workers before (n = 22) and after (n = 19). RESULTS: After implementation of point-of-care testing, there was no significant change in uptake of overall hemoglobin screening (67.9% to 83.0%; p = 0.229), syphilis screening (80.8% to 87.0%; p = 0.282) and CD4+ T-cell testing (84.9% to 83.5%; p = 0.930). Initiation of antiretroviral therapy for treatment eligible women was similar in the weighted analysis before and after, with variability among the sites. Time from HIV diagnosis to treatment initiation decreased (median of 44 days to 17 days; p CONCLUSIONS: Point-of-care CD4+ T-cell enumeration resulted in a decreased time to initiation of antiretroviral therapy among treatment eligible women, without significant increase in testing coverage. Overall hemoglobin and syphilis screening increased. Despite the perception that point-of-care technologies increase access to health services, the variability in results indicate the potential for detrimental effects in some settings. Local context needs to be considered and services restructured to accommodate innovative technologies in order to improve service delivery to expectant mothers

Short-Term Exposure to Tobacco Toxins Alters Expression of Multiple Proliferation Gene Markers in Primary Human Bronchial Epithelial Cell Cultures

The biological effects of only a finite number of tobacco toxins have been studied. Here, we describe exposure of cultures of human bronchial epithelial cells to low concentrations of tobacco carcinogens: nickel sulphate, benzo(b)fluoranthene, N-nitrosodiethylamine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). After a 24-hour exposure, EGFR was expressed in cell membrane and cytoplasm, BCL-2 was expressed only in the irregular nuclei of large atypical cells, MKI67 was expressed in nuclei with no staining in larger cells, cytoplasmic BIRC5 with stronger nuclear staining was seen in large atypical cells, and nuclear TP53 was strongly expressed in all cells. After only a 24-hour exposure, cells exhibited atypical nuclear and cytoplasmic features. After a 48-hour exposure, EGFR staining was localized to the nucleus, BCL-2 was slightly decreased in intensity, BIRC5 was localized to the cytoplasm, and TP53 staining was increased in small and large cells. BCL2L1 was expressed in both the cytoplasm and nuclei of cells at 24- and 48-hour exposures. We illustrate that short-termexposure of a bronchial epithelial cell line to smoking-equivalent concentrations of tobacco carcinogens alters the expression of key proliferation regulatory genes, EGFR, BCL-2, BCL2L1, BIRC5, TP53, and MKI67, similar to that reported in biopsy specimens of pulmonary epithelium described to be preneoplastic lesions

Causes of maternal mortality in Sub-Saharan Africa : a systematic review of studies published from 2015 to 2020

BACKGROUND : Maternal deaths remain high in Sub-Saharan Africa (SSA) and their causes of death must be analysed frequently in this region to guide interventions. METHODS : We conducted a systematic review of studies published from 2015 to 2020 that reported the causes of maternal deaths in 57 SSA countries. The objective was to identify the leading causes of maternal deaths using the international classification of disease – 10th revision, for maternal mortality (ICD-MM). We searched PubMed, WorldCat Discovery Libraries Worldwide (including Medline, Web of Science, LISTA and CNHAL databases), and Google Scholar databases and citations, using the search words “maternal mortality”, “maternal death”, “pregnancy-related death”, “reproductive age mortality” and “causes” as MeSH terms or keywords. The last date of search from all databases was 21 May 2021. We included original research articles published in English and excluded articles that mentioned SSA country names without study results for those countries, studies that reported death from a single cause or assigned causes of death using computer models or incompletely broke down the causes of death. We exported, de-duplicated and screened the searches electronically in EndNote version 20. We selected the final articles by reading the titles, abstracts and full texts. Two authors searched the articles and assessed the risk of bias using a tool adapted from Montoya and others. Data from the articles were extracted onto an Excel worksheet and the deaths classified into ICD-MM groups. Proportions were calculated with 95% confidence intervals and compared for deaths attributed to each cause and ICD-MM group. We compared the results with WHO and Global Burden of Disease (GDB) estimates. RESULTS : We identified 38 studies that reported 11 427 maternal and four incidental deaths. Twenty-one of the third-eight studies were retrospective record reviews. The leading causes of death (proportions and 95% confidence intervals (CI)) were obstetric hemorrhage: 28.8% (95% CI = 26.5%-31.2%), hypertensive disorders in pregnancy: 22.1% (95% CI = 19.9%-24.2%), non-obstetric complications: 18.8% (95% CI = 16.4%- 21.2%) and pregnancy-related infections: 11.5% (95% CI = 9.8%-13.2%). The studies reported few deaths of unknown/undetermined and incidental causes. CONCLUSIONS : Limitations of this review were the failure to access more data from government reports, but the study results compared well with WHO and GDB estimates. Obstetric hemorrhage, hypertensive disorders in pregnancy, non-obstetric complications, and pregnancy-related infections are the leading causes of maternal deaths in SSA. However, deaths from incidental causes are likely under-reported in this region. SSA countries must continue to invest in health information systems that collect and publishes comprehensive, quality, maternal death causes data. A publicly accessible repository of data sets and government reports for causes of maternal death will be helpful in future reviews. This review received no specific funding and was not registered.http://www.jogh.orgam2022School of Health Systems and Public Health (SHSPH

Tenofovir, Lamivudine and Dolutegravir (TLD) among Rural Adolescents in Zimbabwe, a Cautionary Tale.

Tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD) as a safe and more effective single daily dose regimen is rolling out in Africa for people living with HIV. Although access to viral load (VL) testing is improving, patients may still be transitioned to TLD with virological failure and potential drug resistance. We reviewed annual VL test results of 390 children and adolescents who had enrolled in a community-based antiretroviral therapy programme in rural Zimbabwe between 2018 and 2019. VL testing was done by the near point of care Simplified Amplification-based Assays (Diagnostics for the Real World, Sunnyvale California) at Chidamoyo Christian Hospital. Rate of virological suppression (VS) on TLD (VL<1000 copies/ml) was assessed. Overall, 184 children and adolescents on TLD were enrolled in this study. The median (IQR) age was 15 (11-19) years, above half of the participants were female (57%). Prior to switching to TLD, rate of VS was 76% (139/184). After a median (IQR) duration of 6.9 (5.5-9.1) months on TLD, VS was observed in 95% (174/184) of the participants. Of the 10 participants with VL ≥1000 copies/ml on TLD, 90% (9/10) were failing on their previous regimens, 6/9 (67%) having been on boosted protease inhibitor- based regimens. A high rate (95%) of VS was observed among children and adolescents on TLD in rural Zimbabwe. TLD may address the problems of virologic failure and emergence of resistance in Africa. However, longer follow up might be needed to ascertain sustained VS in this vulnerable population

Implementation of Point-of-Care Diagnostics Leads to Variable Uptake of Syphilis, Anemia and CD4+ T-Cell Count Testing in Rural Maternal and Child Health Clinics

Introduction: Anemia, syphilis and HIV are high burden diseases among pregnant women in sub-Saharan Africa. A quasi-experimental study was conducted in four health facilities in Southern Mozambique to evaluate the effect of point-of-care technologies for hemoglobin quantification, syphilis testing and CD4+ T-cell enumeration performed within maternal and child health services on testing and treatment coverage, and assessing acceptability by health workers. Methods: Demographic and testing data on women attending first antenatal care services were extracted from existing records, before (2011; n = 865) and after (2012; n = 808) introduction of point-of-care testing. Study outcomes per health facility were compared using z-tests (categorical variables) and Wilcoxon rank-sum test (continuous variables), while inverse variance weights were used to adjust for possible cluster effects in the pooled analysis. A structured acceptability-assessment interview was conducted with health workers before (n = 22) and after (n = 19). Results: After implementation of point-of-care testing, there was no significant change in uptake of overall hemoglobin screening (67.9% to 83.0%; p = 0.229), syphilis screening (80.8% to 87.0%; p = 0.282) and CD4+ T-cell testing (84.9% to 83.5%; p = 0.930). Initiation of antiretroviral therapy for treatment eligible women was similar in the weighted analysis before and after, with variability among the sites. Time from HIV diagnosis to treatment initiation decreased (median of 44 days to 17 days; p\u3c0.0001). A generally good acceptability for point-of-care testing was seen among health workers. Conclusions: Point-of-care CD4+ T-cell enumeration resulted in a decreased time to initiation of antiretroviral therapy among treatment eligible women, without significant increase in testing coverage. Overall hemoglobin and syphilis screening increased. Despite the perception that point-of-care technologies increase access to health services, the variability in results indicate the potential for detrimental effects in some settings. Local context needs to be considered and services restructured to accommodate innovative technologies in order to improve service delivery to expectant mothers

Changes in causes of pregnancy-related and maternal mortality in Zimbabwe 2007-08 to 2018-19 : findings from two reproductive age mortality surveys

BACKGROUND: Reducing maternal mortality is a priority of Sustainable Development Goal 3.1 which requires frequent epidemiological analysis of trends and patterns of the causes of maternal deaths. We conducted two reproductive age mortality surveys to analyse the epidemiology of maternal mortality in Zimbabwe and analysed the changes in the causes of deaths between 2007-08 and 2018-19. METHODS: We performed a before and after analysis of the causes of death among women of reproductive ages (WRAs) (12-49 years), and pregnant women from the two surveys implemented in 11 districts, selected using multi-stage cluster sampling from each province of Zimbabwe (n=10); an additional district selected from Harare. We calculated mortality incidence rates and incidence rate ratios per 10000 WRAs and pregnant women (with 95% confidence intervals), in international classification of disease groups, using negative binomial models, and compared them between the two surveys. We also calculated maternal mortality ratios, per 100 000 live births, for selected causes of pregnancy-related deaths. RESULTS: We identified 6188 deaths among WRAs and 325 PRDs in 2007-08, and 1856 and 137 respectively in 2018-19. Mortality in the WRAs decreased by 82% in diseases of the respiratory system and 81% in certain infectious or parasitic diseases' groups, which include HIV/AIDS and malaria. Pregnancy-related deaths decreased by 84% in the indirect causes group and by 61% in the direct causes group, and HIV/AIDS-related deaths decreased by 91% in pregnant women. Direct causes of death still had a three-fold MMR than indirect causes (151 vs. 51 deaths per 100 000) in 2018-19. CONCLUSION: Zimbabwe experienced a decline in both direct and indirect causes of pregnancy-related deaths. Deaths from indirect causes declined mainly due to a reduction in HIV/AIDS-related and malaria mortality, while deaths from direct causes declined because of a reduction in obstetric haemorrhage and pregnancy-related infections. Ongoing interventions ought to improve the coverage and quality of maternal care in Zimbabwe, to further reduce deaths from direct causes.The United Kingdom’s Foreign, Commonwealth and Development Office, Department for International Development, UNFPA, UNICEF and WHO Zimbabwe offices, University of Zimbabwe and Ministry of Health.http://www.biomedcentral.com/bmcpublichealthSchool of Health Systems and Public Health (SHSPH