MedZIM: Mediation analysis for Zero-Inflated Mediators with applications to microbiome data

The human microbiome can contribute to the pathogenesis of many complex diseases such as cancer and Alzheimer's disease by mediating disease-leading causal pathways. However, standard mediation analysis is not adequate in the context of microbiome data due to the excessive number of zero values in the data. Zero-valued sequencing reads, commonly observed in microbiome studies, arise for technical and/or biological reasons. Mediation analysis approaches for analyzing zero-inflated mediators are still lacking largely because of challenges raised by the zero-inflated data structure: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are actually not zero (i.e., false zeros). We develop a novel mediation analysis method under the potential-outcomes framework to fill this gap. We show that the mediation effect of the microbiome can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. The first component corresponds to the mediation effect attributable to a unit-change over the positive relative abundance and the second component corresponds to the mediation effect attributable to discrete binary change of the mediator from zero to a non-zero state. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the applications in two real microbiome studies demonstrate that our approach outperforms existing mediation analysis approaches.Comment: Corresponding: Zhigang L

Self-medication with antibiotics for the treatment of menstrual symptoms in southwest Nigeria: a cross-sectional study

Background: Self-medication with antibiotics is an important factor contributing to the development of bacterial antibiotic resistance. The purpose of this study was to evaluate the prevalence of self-medication with antibiotics for the treatment of menstrual symptoms among university women in Southwest Nigeria. Methods: A cross-sectional survey was administered to female undergraduate and graduate students (n = 706) at four universities in Southwest Nigeria in 2008. The universities were selected by convenience and the study samples within each university were randomly selected cluster samples. The survey was self-administered and included questions pertaining to menstrual symptoms, analgesic and antibiotic use patterns, and demographics. Data were analyzed using descriptive statistics and logistic regression. Results: The response rate was 95.4%. Eighty-six percent (95% CI: 83-88%) of participants experienced menstrual symptoms, and 39% (95% CI: 36-43%) reported using analgesics to treat them. Overall, 24% (95% CI: 21-27%) of participants reported self-medicated use of antibiotics to treat the following menstrual symptoms: cramps, bloating, heavy bleeding, headaches, pimples/acne, moodiness, tender breasts, backache, joint and muscle pain. Factors associated with this usage were: lower levels of education (Odds Ratio (OR): 2.8, 95% CI: 1.1-7.1, p-value: 0.03); nonscience major (OR: 1.58, 95% CI: 1.03-2.50, p-value: 0.04); usage of analgesics (OR: 3.17, 95% CI: 2.07-4.86, p-value: <0.001); and mild to extreme heavy bleeding (OR: 1.64, 95% CI: 1.01-2.67, p-value: 0.05) and pimples/acne (OR: 1.57, 95% CI: 0.98-2.54, p-value: 0.06). Ampicillin, tetracycline, ciprofloxacin and metronidazole were used to treat the most symptoms. Doctors or nurses (6%, 95% CI: 4-7%), friends (6%, 95% CI: 4-7%) and family members (7%, 95% CI: 5-8%) were most likely to recommend the use of antibiotics for menstrual symptoms, while these drugs were most often obtained from local chemists or pharmacists (10.2%, 95% CI: 8-12%). Conclusions: This is the first formal study to report that approximately 1 out of 4 university women surveyed in Southwest Nigeria self-medicate with antibiotics to treat menstrual symptoms. This practice could provide monthly, low-dose exposures to antibiotics among users. Further studies are necessary to evaluate the impacts of selfmedication on student health

HIV-Associated Interactions Between Oral Microbiota and Mucosal Immune Cells: Knowledge Gaps and Future Directions

none3openCoker, Modupe O.; Cairo, Cristiana; Garzino-Demo, AlfredoCoker, Modupe O.; Cairo, Cristiana; Garzino-Demo, Alfred

Things must not fall apart: the ripple effects of the COVID-19 pandemic on children in sub-Saharan Africa

Zero to 19 year-old children in sub-Saharan Africa bear a disproportionate proportion of the global burden of communicable and non-communicable diseases. Significant public health gains have been made in the fight against these diseases, however, factors such as underequipped health systems, disease outbreaks, conflict, and political instability continue to challenge prevention and control. The novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduces new challenges to public health programs in sub-Saharan Africa. Of particular concern are programs targeting major conditions among children, such as undernutrition, vaccine-preventable pneumonia and diarrhea, malaria, tuberculosis, HIV, and sickle cell disease. This article focuses on the impact of the COVID-19 pandemic on child health in sub-Saharan Africa. We review the epidemiology of major pediatric diseases and, referencing modeling projections, discuss the short- and long-term impact of the pandemic on major disease control. We deliberate on potential complications of SARS-CoV-2 co-infections/co-morbidities and identify critical social and ethical issues. Furthermore, we highlight the paucity of COVID-19 data and clinical trials in this region and the lack of child participants in ongoing studies. Lastly, approaches and interventions to mitigate the pandemic’s impact on child health outcomes are discussed

Impact of HIV on the Oral Microbiome of Children Living in Sub-Saharan Africa, Determined by Using an rpoC Gene Fragment Metataxonomic Approach

ABSTRACT Children living with HIV have a higher prevalence of oral diseases, including caries, but the mechanisms underlying this higher prevalence are not well understood. Here, we test the hypothesis that HIV infection is associated with a more cariogenic oral microbiome, characterized by an increase in bacteria involved in the pathogenesis of caries. We present data generated from supragingival plaques collected from 484 children representing three exposure groups: (i) children living with HIV (HI), (ii) children who were perinatally exposed but uninfected (HEU), and (iii) unexposed and therefore uninfected children (HUU). We found that the microbiome of HI children is distinct from those of HEU and HUU children and that this distinction is more pronounced in diseased teeth than healthy teeth, suggesting that the impact of HIV is more severe as caries progresses. Moreover, we report both an increase in bacterial diversity and a decrease in community similarity in our older HI cohort compared to our younger HI cohort, which may in part be a prolonged effect of HIV and/or its treatment. Finally, while Streptococcus mutans is often a dominant species in late-stage caries, it tended to be found at lower frequency in our HI cohort than in other groups. Our results highlight the taxonomic diversity of the supragingival plaque microbiome and suggest that broad and increasingly individualistic ecological shifts are responsible for the pathogenesis of caries in children living with HIV, coupled with a diverse and possibly severe impact on known cariogenic taxa that potentially exacerbates caries. IMPORTANCE Since its recognition as a global epidemic in the early 1980s, approximately 84.2 million people have been diagnosed with HIV and 40.1 million people have died from AIDS-related illnesses. The development and increased global availability of antiretroviral treatment (ART) regimens have dramatically reduced the mortality rate of HIV and AIDS, yet approximately 1.5 million new infections were reported in 2021, 51% of which are in sub-Saharan Africa. People living with HIV have a higher prevalence of caries and other chronic oral diseases, the mechanisms of which are not well understood. Here, we used a novel genetic approach to characterize the supragingival plaque microbiome of children living with HIV and compared it to the microbiomes of uninfected and perinatally exposed children to better understand the role of oral bacteria in the etiology of tooth decay in the context of HIV exposure and infection

Age-specific associations with dental caries in HIV-infected, exposed but uninfected and HIV-unexposed uninfected children in Nigeria

Abstract Background HIV infection and its management confer a substantial health burden to affected individuals and have been associated with increased risk of oral and dental diseases. In this study, we sought to quantify HIV-associated differences in the prevalence and severity of dental caries in the primary and permanent dentition of 4–11-year-old Nigerian Children. Methods We used clinical, laboratory, demographic, and behavioral data obtained from an ongoing cohort study of age-matched HIV-infected (HI, n = 181), HIV-exposed-but-uninfected (HEU, n = 177), and HIV-unexposed-and-uninfected (HUU, n = 186) children. Measures of dental caries experience (i.e., prevalence and severity) were based on dmft/DMFT indices recorded by trained and calibrated clinical examiners. Differences in primary and permanent dentition caries experience between HI, HEU, and HUU were estimated using multivariable logistic and negative binomial regression modeling. Results HI children had significantly higher caries experience (33%) compared to HEU (15%) and HUU (22%) children. This difference persisted in fully adjusted analyses [odds ratio (OR) = 1.6; 95% confidence interval (CI) = 1.0–2.6], was most pronounced in the permanent dentition (OR = 3.4; 95% CI = 1.2–9.5), and mirrored differences in caries severity. While molars were predominantly affected in both primary and permanent dentitions, caries lesion patterns differed between dentitions. Caries severity was significantly associated with hypoplastic primary teeth, gingival inflammation, and lower CD4 counts. Conclusions We found that the higher prevalence and severity of dental caries among HI children was driven by increased burden of permanent dentition caries compared to their uninfected counterparts. The dentition-specific associations identified in this study highlight the need to design and implement age-specific caries prevention strategies. These may include intensified oral hygiene regimens aimed at mitigating the cariogenic impact of hyposalivation among HI children. Similarly, the long-lasting impacts of developmental defects of the enamel in the primary and permanent dentitions must not be ignored

MarZIC: A Marginal Mediation Model for Zero-Inflated Compositional Mediators with Applications to Microbiome Data

Background: The human microbiome can contribute to pathogeneses of many complex diseases by mediating disease-leading causal pathways. However, standard mediation analysis methods are not adequate to analyze the microbiome as a mediator due to the excessive number of zero-valued sequencing reads in the data and that the relative abundances have to sum to one. The two main challenges raised by the zero-inflated data structure are: (a) disentangling the mediation effect induced by the point mass at zero; and (b) identifying the observed zero-valued data points that are not zero (i.e., false zeros). Methods: We develop a novel marginal mediation analysis method under the potential-outcomes framework to address the issues. We also show that the marginal model can account for the compositional structure of microbiome data. Results: The mediation effect can be decomposed into two components that are inherent to the two-part nature of zero-inflated distributions. With probabilistic models to account for observing zeros, we also address the challenge with false zeros. A comprehensive simulation study and the application in a real microbiome study showcase our approach in comparison with existing approaches. Conclusions: When analyzing the zero-inflated microbiome composition as the mediators, MarZIC approach has better performance than standard causal mediation analysis approaches and existing competing approach

Dental caries and its association with the oral microbiomes and HIV in young children—Nigeria (DOMHaIN): a cohort study

Abstract Background This study seeks to understand better the mechanisms underlying the increased risk of caries in HIV-infected school-aged Nigerian children by examining the relationship between the plaque microbiome and perinatal HIV infection and exposure. We also seek to investigate how perinatal HIV infection and exposure impact tooth-specific microbiomes\u27 role on caries disease progression. Methods The participants in this study were children aged 4 to 11 years recruited from the University of Benin Teaching Hospital (UBTH), Nigeria, between May to November 2019. Overall, 568 children were enrolled in three groups: 189 HIV-infected (HI), 189 HIV-exposed but uninfected (HEU) and 190 HIV-unexposed and uninfected (HUU) as controls at visit 1 with a 2.99% and 4.90% attrition rate at visit 2 and visit 3 respectively. Data were obtained with standardized questionnaires. Blood samples were collected for HIV, HBV and HCV screening; CD4, CD8 and full blood count analysis; and plasma samples stored for future investigations; oral samples including saliva, buccal swabs, oropharyngeal swab, tongue swab, dental plaque were collected aseptically from participants at different study visits. Conclusions Results from the study will provide critical information on how HIV exposure, infection, and treatment, influence the oral microbiome and caries susceptibility in children. By determining the effect on community taxonomic structure and gene expression of dental microbiomes, we will elucidate mechanisms that potentially create a predisposition for developing dental caries. As future plans, the relationship between respiratory tract infections, immune and inflammatory markers with dental caries in perinatal HIV infection and exposure will be investigated