Epigenetics, and Human Biology and Health Responses to Modernization in the Samoan Archipelago

Epigenetic mechanisms offer explanations for how environmental exposures at critical life periods may affect human biological and disease phenotypes. Incorporation of epigenetic approaches into research on health consequences of societal transitions may increase understanding of the complex biobehavioral factors influencing changing populations. Description of present and planned genetic epidemiology research, including epigenetic studies, among Samoans experiencing economic modernization and globalization offer examples for progress in knowledge of population health transitions

Decision-Model Estimation of the Age-Specific Disability Weight for Schistosomiasis Japonica: A Systematic Review of the Literature

Schistosomiasis is among the most prevalent parasitic infections worldwide. However, current Global Burden of Disease (GBD) disability-adjusted life year estimates indicate that its population-level impact is negligible. Recent studies suggest that GBD methodologies may significantly underestimate the burden of parasitic diseases, including schistosomiasis. Furthermore, strain-specific disability weights have not been established for schistosomiasis, and the magnitude of human disease burden due to Schistosoma japonicum remains controversial. We used a decision model to quantify an alternative disability weight estimate of the burden of human disease due to S. japonicum. We reviewed S. japonicum morbidity data, and constructed decision trees for all infected persons and two age-specific strata, <15 years (y) and ≥15 y. We conducted stochastic and probabilistic sensitivity analyses for each model. Infection with S. japonicum was associated with an average disability weight of 0.132, with age-specific disability weights of 0.098 (<15 y) and 0.186 (≥15 y). Re-estimated disability weights were seven to 46 times greater than current GBD measures; no simulations produced disability weight estimates lower than 0.009. Nutritional morbidities had the greatest contribution to the S. japonicum disability weight in the <15 y model, whereas major organ pathologies were the most critical variables in the older age group. GBD disability weights for schistosomiasis urgently need to be revised, and species-specific disability weights should be established. Even a marginal increase in current estimates would result in a substantial rise in the estimated global burden of schistosomiasis, and have considerable implications for public health prioritization and resource allocation for schistosomiasis research, monitoring, and control

Assessing the Impact of Misclassification Error on an Epidemiological Association between Two Helminthic Infections

Hookworm, roundworm, and whipworm are collectively known as soil-transmitted helminths. These worms are prevalent in most of the developing countries along with another parasitic infection called schistosomiasis. The tests commonly used to detect infection with these worms are less than 100% accurate. This leads to misclassification of infection status since these tests cannot always correctly indentify infection. We conducted an epidemiological study where such a test, the Kato-Katz technique, was used. In our study we tried to show how misclassification error can influence the association between soil-transmitted helminth infection and schistosomiasis in humans. We used a statistical technique to calculate epidemiological measures of association after correcting for the inaccuracy of the test. Our results show that there is a major difference between epidemiological measures of association before and after the correction of the inaccuracy of the test. After correction of the inaccuracy of the test, soil-transmitted helminth infection was found to be associated with increased risk of acquiring schistosomiasis. This has major public health implications since effective control of one worm can lead to reduction in the occurrence of another and help to reduce the overall burden of worm infection in affected regions

Redefining disease emergence to improve prioritization and macro-ecological analyses

AbstractMicrobial infections are as old as the hosts they sicken, but interest in the emergence of pathogens and the diseases they cause has been accelerating rapidly. The term ‘emerging infectious disease’ was coined in the mid-1900s to describe changes in disease dynamics in the modern era. Both the term and the phenomena it is meant to characterize have evolved and diversified over time, leading to inconsistencies and confusion. Here, we review the evolution of the term ‘emerging infectious disease’ (EID) in the literature as applied to human hosts. We examine the pathways (e.g., speciation or strain differentiation in the causative agent vs. rapid geographic expansion of an existing pathogen) by which diseases emerge. We propose a new framework for disease and pathogen emergence to improve prioritization. And we illustrate how the operational definition of an EID affects conclusions concerning the pathways by which diseases emerge and the ecological and socioeconomic drivers that elicit emergence. As EIDs appear to be increasing globally, and resources for science level off or decline, the research community is pushed to prioritize its focus on the most threatening diseases, riskiest potential pathogens, and the places they occur. The working definition of emerging infectious diseases and pathogens plays a crucial role in prioritization, but we argue that the current definitions may be impeding these efforts. We propose a new framework for classifying pathogens and diseases as “emerging” that distinguishes EIDs from emerging pathogens and novel potential pathogens. We suggest prioritization of: 1) EIDs for adaptation and mitigation, 2) emerging pathogens for preventive measures, and 3) novel potential pathogens for intensive surveillance

PcG Proteins, DNA Methylation, and Gene Repression by Chromatin Looping

Many DNA hypermethylated and epigenetically silenced genes in adult cancers are Polycomb group (PcG) marked in embryonic stem (ES) cells. We show that a large region upstream (∼30 kb) of and extending ∼60 kb around one such gene, GATA-4, is organized—in Tera-2 undifferentiated embryonic carcinoma (EC) cells—in a topologically complex multi-loop conformation that is formed by multiple internal long-range contact regions near areas enriched for EZH2, other PcG proteins, and the signature PcG histone mark, H3K27me3. Small interfering RNA (siRNA)–mediated depletion of EZH2 in undifferentiated Tera-2 cells leads to a significant reduction in the frequency of long-range associations at the GATA-4 locus, seemingly dependent on affecting the H3K27me3 enrichments around those chromatin regions, accompanied by a modest increase in GATA-4 transcription. The chromatin loops completely dissolve, accompanied by loss of PcG proteins and H3K27me3 marks, when Tera-2 cells receive differentiation signals which induce a ∼60-fold increase in GATA-4 expression. In colon cancer cells, however, the frequency of the long-range interactions are increased in a setting where GATA-4 has no basal transcription and the loops encompass multiple, abnormally DNA hypermethylated CpG islands, and the methyl-cytosine binding protein MBD2 is localized to these CpG islands, including ones near the gene promoter. Removing DNA methylation through genetic disruption of DNA methyltransferases (DKO cells) leads to loss of MBD2 occupancy and to a decrease in the frequency of long-range contacts, such that these now more resemble those in undifferentiated Tera-2 cells. Our findings reveal unexpected similarities in higher order chromatin conformation between stem/precursor cells and adult cancers. We also provide novel insight that PcG-occupied and H3K27me3-enriched regions can form chromatin loops and physically interact in cis around a single gene in mammalian cells. The loops associate with a poised, low transcription state in EC cells and, with the addition of DNA methylation, completely repressed transcription in adult cancer cells

Suggestive Linkage Detected for Blood Pressure Related Traits on 2q and 22q in the Population on the Samoan Islands

Background High blood pressure or hypertension is a major risk factor involved in the development of cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing five blood pressure related traits including the quantitative traits systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP), the dichotomous trait hypertension (HT) and the bivariate quantitative trait SBP-DBP in families residing in American Samoa and Samoa, as well as in the combined sample from the two polities. We adjusted the traits for a number of environmental covariates such as smoking, alcohol consumption, physical activity and material life style. Results We found suggestive univariate linkage for SBP on chromosome 2q35-q37 (LOD 2.4) and for PP on chromosome 22q13 (LOD 2.2), two chromosomal regions that recently have been associated with SBP and PP, respectively. Conclusion We have detected additional evidence for a recently reported locus associated with SBP on chromosome 2q and a susceptibility locus for PP on chromosome 22q. However, differences observed between the results from our three partly overlapping genetically homogenous study samples from the Samoan islands suggest that additional studies should be performed in order to verify these results

Stratified randomization controls better for batch effects in 450K methylation analysis: a cautionary tale

Background: Batch effects in DNA methylation microarray experiments can lead to spurious results if not properly handled during the plating of samples. Methods: Two pilot studies examining the association of DNA methylation patterns across the genome with obesity in Samoan men were investigated for chip- and row-specific batch effects. For each study, the DNA of 46 obese men and 46 lean men were assayed using Illumina's Infinium HumanMethylation450 BeadChip. In the first study (Sample One), samples from obese and lean subjects were examined on separate chips. In the second study (Sample Two), the samples were balanced on the chips by lean/obese status, age group, and census region. We used methylumi, watermelon, and limma R packages, as well as ComBat, to analyze the data. Principal component analysis and linear regression were respectively employed to identify the top principal components and to test for their association with the batches and lean/obese status. To identify differentially methylated positions (DMPs) between obese and lean males at each locus, we used a moderated t-test.Results: Chip effects were effectively removed from Sample Two but not Sample One. In addition, dramatic differences were observed between the two sets of DMP results. After removing'' batch effects with ComBat, Sample One had 94,191 probes differentially methylated at a q-value threshold of 0.05 while Sample Two had zero differentially methylated probes. The disparate results from Sample One and Sample Two likely arise due to the confounding of lean/obese status with chip and row batch effects.Conclusion: Even the best possible statistical adjustments for batch effects may not completely remove them. Proper study design is vital for guarding against spurious findings due to such effects

Effectiveness of the baby-friendly community initiative in promoting exclusive breastfeeding among HIV negative and positive mothers: A randomized controlled trial in Koibatek Sub-County, Baringo, Kenya

Background: Although the baby-friendly community initiative (BFCI) has been proposed as a community-level approach to improve infant feeding practices, there is little data on its variation in effectiveness by HIV status. We conducted a study to determine the effectiveness of BFCI in changing knowledge and attitudes towards exclusive breastfeeding (EBF) and increasing the rates among HIV negative and HIV positive women in rural Kenya. Methods: A community-based cluster-randomized controlled trial was implemented from April 2015 to December 2016 among 901 women enrolled across 13 clusters. The intervention groups received a minimum of 12 personalized home-based counselling sessions on infant feeding by trained community health volunteers from their first or second trimester of pregnancy until 6 months postpartum. Other interventions included education sessions at maternal child clinics, mother-to-mother support group meetings and bi-monthly baby-friendly gatherings targeting influencers. The control group received standard health education at the facility and during monthly routine home visits by community health volunteers not trained on BFCI. Primary outcome measures were the rates of EBF at week 1, months 2, 4 and 6 postpartum. Secondary outcomes included knowledge and attitudes regarding breastfeeding for HIV-exposed infants. Statistical methods included analysis of covariance and logistic regression. Results: At 6 months, EBF rates among HIV negative mothers were significantly higher in the BFCI intervention arm compared to the control arm (81.7% versus 42.2% p = 0.001). HIV positive mothers in the intervention arm had higher EBF rates at 6 months than the control but the difference was not statistically significant (81.8% versus 58.4%; p = 0.504). In HIV negative group, there was greater knowledge regarding EBF for HIV-exposed infants in the intervention arm than in the control (92.1% versus 60.7% p = 0.001). Among HIV positive mothers, such knowledge was high among both the intervention and control groups (96% versus 100%, p &gt; 0.1). HIV negative and positive mothers in the intervention arm had more favourable attitudes regarding EBF for HIV-exposed infants than the control (84.5% versus 62.1%, p = 0.001) and (94.6% versus 53.8% to p = 0.001) respectively. Conclusions: BFCI interventions can complement facility-based interventions to improve exclusive and continued breastfeeding knowledge, attitudes, and behaviours among HIV negative and positive women