Direct inference and control of genetic population structure from RNA sequencing data

RNAseq data can be used to infer genetic variants, yet its use for estimating genetic population structure remains underexplored. Here, we construct a freely available computational tool (RGStraP) to estimate RNAseq-based genetic principal components (RG-PCs) and assess whether RG-PCs can be used to control for population structure in gene expression analyses. Using whole blood samples from understudied Nepalese populations and the Geuvadis study, we show that RG-PCs had comparable results to paired array-based genotypes, with high genotype concordance and high correlations of genetic principal components, capturing subpopulations within the dataset. In differential gene expression analysis, we found that inclusion of RG-PCs as covariates reduced test statistic inflation. Our paper demonstrates that genetic population structure can be directly inferred and controlled for using RNAseq data, thus facilitating improved retrospective and future analyses of transcriptomic data

Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial

Background: We evaluated efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in HIV-infected patients with cryptosporidiosis. Methods: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in Part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched HIV-infected individuals without cryptosporidiosis. Results: Twenty Part A and 10 Part B participants completed the study ATP. Almost all Part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the Part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared to the placebo group. Over the inpatient period, compared to those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit: 3.82), total stool weight decreased by 45.3 g (p=0.37), and number of diarrheal episodes increased by 2.32 (p=0.87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. Three CFZ and 1 placebo subjects died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than Part B controls. Conclusion: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy

Weight Status and Behavioral Problems among Very Young Children in Chile

BACKGROUND/OBJECTIVES:Our objective was to explore the association between weight status and behavioral problems in children before school age. We examined whether the association between weight status and behavioral problems varied by age and sex. SUBJECTS/METHODS:This study used cross-sectional data from a nationally-representative sample of children and their families in Chile (N = 11,207). These children were selected using a cluster-stratified random sampling strategy. Data collection for this study took place in 2012 when the children were 1.5-6 years of age. We used multivariable analyses to examine the association between weight status and behavioral problems (assessed using the Child Behavior Checklist), while controlling for child's sex, indigenous status, birth weight, and months breastfed; primary caregiver's BMI and education level; and household wealth. RESULTS:Approximately 24% of our sample was overweight or obese. Overweight or obese girls showed more behavioral problems than normal weight girls at age 6 (β = 0.270 SD, 95% CI = 0.047, 0.493, P = 0.018). Among boys age 1 to 5 years, overweight/obesity was associated with a small reduction in internalizing behaviors (β = -0.09 SD, 95% CI = -0.163, -0.006, P = 0.034). CONCLUSIONS:Our data suggest that the associations between weight status and behavioral problems vary across age and sex