Publications by authors named "Saunak Sen"

106 Publications

Identification of fibronectin 1 as a candidate genetic modifier in a Col4a1 mutant mouse model of Gould syndrome.

Dis Model Mech 2021 Apr 26;14(4). Epub 2021 Apr 26.

Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143, USA.

Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. In recent years, patient advocacy and family support groups have united under the name of Gould syndrome. The manifestations of Gould syndrome are highly variable, and animal studies suggest that allelic heterogeneity and genetic context contribute to the clinical variability. We previously characterized a mouse model of Gould syndrome caused by a Col4a1 mutation in which the severities of ocular anterior segment dysgenesis (ASD), myopathy and intracerebral hemorrhage (ICH) were dependent on genetic background. Here, we performed a genetic modifier screen to provide insight into the mechanisms contributing to Gould syndrome pathogenesis and identified a single locus [modifier of Gould syndrome 1 (MoGS1)] on Chromosome 1 that suppressed ASD. A separate screen showed that the same locus ameliorated myopathy. Interestingly, MoGS1 had no effect on ICH, suggesting that this phenotype could be mechanistically distinct. We refined the MoGS1 locus to a 4.3 Mb interval containing 18 protein-coding genes, including Fn1, which encodes the extracellular matrix component fibronectin 1. Molecular analysis showed that the MoGS1 locus increased Fn1 expression, raising the possibility that suppression is achieved through a compensatory extracellular mechanism. Furthermore, we found evidence of increased integrin-linked kinase levels and focal adhesion kinase phosphorylation in Col4a1 mutant mice that is partially restored by the MoGS1 locus, implicating the involvement of integrin signaling. Taken together, our results suggest that tissue-specific mechanistic heterogeneity contributes to the variable expressivity of Gould syndrome and that perturbations in integrin signaling may play a role in ocular and muscular manifestations.
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http://dx.doi.org/10.1242/dmm.048231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106953PMC
April 2021

Organophosphate Flame Retardants, Highly Fluorinated Chemicals, and Biomarkers of Placental Development and Disease during Mid-Gestation.

Toxicol Sci 2021 Mar 2. Epub 2021 Mar 2.

University of California, San Francisco, Program on Reproductive Health and the Environment, San Francisco, CA, USA.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n = 62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50-100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3-2.8 (95% confidence limits from 1.2-3.1) ng/mL compared to ≤ 0.5 ng/mL for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5-3.4) and 3.6 (95% CI: 2.2-3.1) ng/mL, respectively, compared to < 1 ng/mL for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period.
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http://dx.doi.org/10.1093/toxsci/kfab028DOI Listing
March 2021

Estimating the Effect of Social Distancing Interventions on COVID-19 in the United States.

Am J Epidemiol 2021 Jan 7. Epub 2021 Jan 7.

MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, United Kingdom.

Since its global emergence in 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused multiple epidemics in the United States. Because medical treatments for the virus are still emerging and a vaccine is not yet available, state and local governments have sought to limit its spread by enacting various social distancing interventions such as school closures and lockdown, but the effectiveness of these interventions is unknown. We applied an established, semi-mechanistic Bayesian hierarchical model of these interventions on SARS-CoV-2 spread in Europe to the United States, using case fatalities from February 29, 2020 up to April 25, 2020, when some states began reversing their interventions. We estimated the effect of interventions across all states, contrasted the estimated reproduction number, Rt, for each state before and after lockdown, and contrasted predicted future fatalities with actual fatalities as a check on the model's validity. Overall, school closures and lockdown are the only interventions modeled that have a reliable impact on Rt, and lockdown appears to have played a key role in reducing Rt below 1.0. We conclude that reversal of lockdown, without implementation of additional, equally effective interventions, will enable continued, sustained transmission of SARS-CoV-2 in the United States.
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http://dx.doi.org/10.1093/aje/kwaa293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929448PMC
January 2021

Importance of Multiple Reinforcing Comments and Areas for Change in Optimizing Dietary and Exercise Self-Monitoring Feedback in Behavioral Weight Loss Programs: Factorial Design.

J Med Internet Res 2020 11 23;22(11):e18104. Epub 2020 Nov 23.

Arnold School of Public Health, University of South Carolina, Columbia, SC, United States.

Background: Individualized dietary and physical activity self-monitoring feedback is a core element of behavioral weight loss interventions and is associated with clinically significant weight loss. To our knowledge, no studies have evaluated individuals' perspectives on the composition of feedback messages or the effect of feedback composition on the motivation to self-monitor.

Objective: This study aims to assess the perceptions of feedback emails as a function of the number of comments that reinforce healthy behavior and the number of areas for change (ie, behavioral changes that the individual might make to have an impact on weight) identified.

Methods: Emailed feedback followed a factorial design with 2 factors (ie, reinforcing comments and areas for change), each with 3 levels (ie, 1, 4, or 8 comments). A total of 250 adults with overweight or obesity who were interested in weight loss were recruited from the Qualtrics research panel. Participants read 9 emails presented in a random order. For each email, respondents answered 8 questions about the likelihood to self-monitor in the future, motivation for behavioral change, and perceptions of the counselor and the email. A mixed effects ordinal logistic model was used to compute conditional odds ratios and predictive margins (ie, average predicted probability) on a 5-point Likert response scale to investigate the optimal combination level of the 2 factors.

Results: Emails with more reinforcing comments or areas for change were better received, with small incremental benefits for 8 reinforcing comments or areas for change versus 4 reinforcing comments or areas for change. Interactions indicated that the best combination for 3 of 8 outcomes assessed (ie, motivation to make behavioral changes, counselor's concern for their welfare, and the perception that the counselor likes them) was the email with 8 reinforcing comments and 4 areas for change. Emails with 4 reinforcing comments and 4 areas for change resulted in the highest average probability of individuals who reported being very likely to self-monitor in the future.

Conclusions: The study findings suggest how feedback might be optimized for efficacy. Future studies should explore whether the composition of feedback email affects actual self-monitoring performance.
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http://dx.doi.org/10.2196/18104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685695PMC
November 2020

Racial/ethnic and geographic differences in polybrominated diphenyl ether (PBDE) levels across maternal, placental, and fetal tissues during mid-gestation.

Sci Rep 2020 07 22;10(1):12247. Epub 2020 Jul 22.

Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, Mailstop 0132, 550 16th Street, 7th Floor, San Francisco, CA, 94143, USA.

Prenatal polybrominated diphenyl ether (PBDE) exposures are a public health concern due to their persistence and potential for reproductive and developmental harm. However, we have little information about the extent of fetal exposures during critical developmental periods and the variation in exposures for groups that may be more highly exposed, such as communities of color and lower socioeconomic status (SES). To characterize maternal-fetal PBDE exposures among potentially vulnerable groups, PBDE levels were examined in the largest sample of matched maternal serum, placenta, and fetal liver tissues during mid-gestation among a geographically, racially/ethnically, and socially diverse population of pregnant women from Northern California and the Central Valley (n = 180; 2014-16). Maternal-fetal PBDE levels were compared to population characteristics using censored Kendall's tau correlation and linear regression. PBDEs were commonly detected in all biomatrices. Before lipid adjustment, wet-weight levels of all four PBDE congeners were highest in the fetal liver (p < 0.001), whereas median PBDE levels were significantly higher in maternal serum than in the fetal liver or placenta after lipid-adjustment (p < 0.001). We also found evidence of racial/ethnic disparities in PBDE exposures (Non-Hispanic Black > Latina/Hispanic > Non-Hispanic White > Asian/Pacific Islander/Other; p < 0.01), with higher levels of BDE-100 and BDE-153 among non-Hispanic Black women compared to the referent group (Latina/Hispanic women). In addition, participants living in Fresno/South Central Valley had 34% (95% CI: - 2.4 to 84%, p = 0.07) higher wet-weight levels of BDE-47 than residents living in the San Francisco Bay Area. PBDEs are widely detected and differentially distributed in maternal-fetal compartments. Non-Hispanic Black pregnant women and women from Southern Central Valley geographical populations may be more highly exposed to PBDEs. Further research is needed to identify sources that may be contributing to differential exposures and associated health risks among these vulnerable populations.
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http://dx.doi.org/10.1038/s41598-020-69067-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376153PMC
July 2020

Association of polybrominated diphenyl ether (PBDE) levels with biomarkers of placental development and disease during mid-gestation.

Environ Health 2020 06 3;19(1):61. Epub 2020 Jun 3.

Program on Reproductive Health and the Environment, UCSF Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, Mailstop 0132, 550 16th Street, 7th Floor, San Francisco, CA, 94143, USA.

Background: Polybrominated diphenyl ether (PBDE) exposures have been associated with adverse pregnancy outcomes. A hypothesized mechanism is via alterations in placental development and function. However, we lack biomarkers that can be used as early indicators of maternal/fetal response to PBDE exposures and/or perturbations in placental development or function.

Methods: To evaluate the relationship between PBDE levels and placental biomarkers during mid-gestation of human pregnancy (n = 62), we immunolocalized three molecules that play key roles in cytotrophoblast (CTB) differentiation and interstitial/endovascular uterine invasion-integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and metalloproteinase-1 (MMP1)-and assessed three morphological parameters as potential indicators of pathological alterations using H&E-stained tissues-leukocyte infiltration, fibrinoid deposition, and CTB endovascular invasion. We evaluated associations between placental PBDE levels and of biomarkers of placental development and disease using censored Kendall's tau correlation and linear regression methods.

Results: PBDEs were detected in all placental samples. We observed substantial variation in antigen expression and morphological endpoints across placental regions. We observed an association between PBDE concentrations and immunoreactivity of endovascular CTB staining with anti-ITGA1 (inverse) or interstitial CTBs staining with anti-CDH5 (positive).

Conclusions: We found several molecular markers that may be sensitive placental indicators of PBDE exposure. Further, this indicates that placental biomarkers of development and disease could be useful barometers of exposure to PBDEs, a paradigm that could be extended to other environmental chemicals and placental stage-specific antigens.
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http://dx.doi.org/10.1186/s12940-020-00617-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268484PMC
June 2020

Matrix Linear Models for High-Throughput Chemical Genetic Screens.

Genetics 2019 08 26;212(4):1063-1073. Epub 2019 Jun 26.

Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163

We develop a flexible and computationally efficient approach for analyzing high-throughput chemical genetic screens. In such screens, a library of genetic mutants is phenotyped in a large number of stresses. Typically, interactions between genes and stresses are detected by grouping the mutants and stresses into categories, and performing modified -tests for each combination. This approach does not have a natural extension if mutants or stresses have quantitative or nonoverlapping annotations (, if conditions have doses or a mutant falls into more than one category simultaneously). We develop a matrix linear model (MLM) framework that allows us to model relationships between mutants and conditions in a simple, yet flexible, multivariate framework. It encodes both categorical and continuous relationships to enhance detection of associations. We develop a fast estimation algorithm that takes advantage of the structure of MLMs. We evaluate our method's performance in simulations and in an chemical genetic screen, comparing it with an existing univariate approach based on modified -tests. We show that MLMs perform slightly better than the univariate approach when mutants and conditions are classified in nonoverlapping categories, and substantially better when conditions can be ordered in dosage categories. Therefore, it is an attractive alternative to current methods, and provides a computationally scalable framework for larger and complex chemical genetic screens. A Julia language implementation of MLMs and the code used for this paper are available at https://github.com/janewliang/GeneticScreen.jl and https://bitbucket.org/jwliang/mlm_gs_supplement, respectively.
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http://dx.doi.org/10.1534/genetics.119.302299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707451PMC
August 2019

Cleaning Genotype Data from Diversity Outbred Mice.

G3 (Bethesda) 2019 05 7;9(5):1571-1579. Epub 2019 May 7.

The Jackson Laboratory, Bar Harbor, Maine 04609.

Data cleaning is an important first step in most statistical analyses, including efforts to map the genetic loci that contribute to variation in quantitative traits. Here we illustrate approaches to quality control and cleaning of array-based genotyping data for multiparent populations (experimental crosses derived from more than two founder strains), using MegaMUGA array data from a set of 291 Diversity Outbred (DO) mice. Our approach employs data visualizations that can reveal problems at the level of individual mice or with individual SNP markers. We find that the proportion of missing genotypes for each mouse is an effective indicator of sample quality. We use microarray probe intensities for SNPs on the X and Y chromosomes to confirm the sex of each mouse, and we use the proportion of matching SNP genotypes between pairs of mice to detect sample duplicates. We use a hidden Markov model (HMM) reconstruction of the founder haplotype mosaic across each mouse genome to estimate the number of crossovers and to identify potential genotyping errors. To evaluate marker quality, we find that missing data and genotyping error rates are the most effective diagnostics. We also examine the SNP genotype frequencies with markers grouped according to their minor allele frequency in the founder strains. For markers with high apparent error rates, a scatterplot of the allele-specific probe intensities can reveal the underlying cause of incorrect genotype calls. The decision to include or exclude low-quality samples can have a significant impact on the mapping results for a given study. We find that the impact of low-quality markers on a given study is often minimal, but reporting problematic markers can improve the utility of the genotyping array across many studies.
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http://dx.doi.org/10.1534/g3.119.400165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505173PMC
May 2019

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.

Clin Exp Allergy 2019 06 15;49(6):789-798. Epub 2019 Feb 15.

Division of Pediatric Pulmonary Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh, Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response.

Objective: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings.

Methods: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations.

Results: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified.

Conclusions And Clinical Relevance: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.
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http://dx.doi.org/10.1111/cea.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054824PMC
June 2019

Acculturation is associated with asthma burden and pulmonary function in Latino youth: The GALA II study.

J Allergy Clin Immunol 2019 05 22;143(5):1914-1922. Epub 2019 Jan 22.

Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, Calif.

Background: Acculturation is an important predictor of asthma in Latino youth, specifically Mexican Americans. Less is known about acculturation and pulmonary function measures.

Objective: We sought to estimate the association of acculturation measures with asthma and pulmonary function in Latino youth and determine whether this association varies across Latino subgroups.

Methods: We included 1849 Latinos (302 Caribbean Spanish, 193 Central or South Americans, 1136 Mexican Americans, and 218 other Latino children) aged 8 to 21 years from 4 urban regions in the United States. Acculturation measures include nativity status, age of immigration, language of preference, and generation in the United States. We used multivariable logistic and linear regression models to quantify the association of acculturation factors with the presence of asthma (case-control study) and pulmonary function (case-only study), adjusting for demographic, socioenvironmental, and clinical variables.

Results: For all acculturation measures (nativity status, age of immigration, language of preference, and generation in the United States), greater levels of acculturation were associated with greater odds of asthma. Among cases, high (English preference) and medium (equal preference for Spanish and English) levels of language acculturation were associated with decreased bronchodilator response compared with low (Spanish preference) levels (P = .009 and .02, respectively). Similarly, high language acculturation was associated with increased FEV compared with low language acculturation (P = .02). There was insufficient evidence of heterogeneity for associations across Latino subgroups.

Conclusions: Acculturation was associated with diagnosed asthma and pulmonary function in Latino children and is an important factor to consider in the management of Latino youth with asthma.
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http://dx.doi.org/10.1016/j.jaci.2018.12.1015DOI Listing
May 2019

R/qtl2: Software for Mapping Quantitative Trait Loci with High-Dimensional Data and Multiparent Populations.

Genetics 2019 02 27;211(2):495-502. Epub 2018 Dec 27.

The Jackson Laboratory, Bar Harbor, Maine 04609.

R/qtl2 is an interactive software environment for mapping quantitative trait loci (QTL) in experimental populations. The R/qtl2 software expands the scope of the widely used R/qtl software package to include multiparent populations derived from more than two founder strains, such as the Collaborative Cross and Diversity Outbred mice, heterogeneous stocks, and MAGIC plant populations. R/qtl2 is designed to handle modern high-density genotyping data and high-dimensional molecular phenotypes, including gene expression and proteomics. R/qtl2 includes the ability to perform genome scans using a linear mixed model to account for population structure, and also includes features to impute SNPs based on founder strain genomes and to carry out association mapping. The R/qtl2 software provides all of the basic features needed for QTL mapping, including graphical displays and summary reports, and it can be extended through the creation of add-on packages. R/qtl2, which is free and open source software written in the R and C++ programming languages, comes with a test framework.
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http://dx.doi.org/10.1534/genetics.118.301595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366910PMC
February 2019

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

J Allergy Clin Immunol 2019 03 7;143(3):957-969. Epub 2018 Sep 7.

Veterans Caribbean Health Care System, San Juan, Puerto Rico.

Background: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.

Objective: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.

Methods: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.

Results: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10, combined P = 2.6 × 10). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.

Conclusion: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2016.08.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927816PMC
March 2019

Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma.

Thorax 2018 11 13;73(11):1041-1048. Epub 2018 Jun 13.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Background: Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported.

Objectives: Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature.

Methods: We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines.

Results: The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures.

Conclusions: Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225993PMC
November 2018

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Am J Respir Crit Care Med 2018 06;197(12):1552-1564

5 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Rationale: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

Objectives: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

Methods: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

Measurements And Main Results: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10) and suggestive (P < 7.06 × 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

Conclusions: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
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http://dx.doi.org/10.1164/rccm.201712-2529OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006403PMC
June 2018

Developmental PBDE Exposure and IQ/ADHD in Childhood: A Systematic Review and Meta-analysis.

Environ Health Perspect 2017 08 3;125(8):086001. Epub 2017 Aug 3.

Program on Reproductive Health and the Environment, University of California , San Francisco, San Francisco, California, USA.

Background: In the United States, one in six children are affected by neurodevelopmental disorders, and polybrominated diphenyl ethers (PBDEs) in flame-retardant chemicals are measured ubiquitously in children.

Objective: We conducted a systematic a systematic review regarding developmental exposure to PBDEs and intelligence or Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans.

Methods: We searched articles published up to 26 September 2016, and included original studies that quantified exposures to PBDEs incurred any time in proximity to conception or during , perinatal, or childhood time periods. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide systematic review methodology. We established criteria in advance to identify studies that could be combined using random effects meta-analyses (DerSimonian-Laird method).

Results: Fifteen studies met the inclusion criteria; 10 studies met the criteria for intelligence and nine for attention-related problems. We rated studies generally with "low" to "probably low" risk of bias and rated the overall body of evidence as "moderate" quality with "sufficient" evidence for an association between Intelligence Quotient (IQ) and PBDEs. Our meta-analysis of four studies estimated a 10-fold increase (in other words, times 10) in PBDE exposure associated with a decrement of 3.70 IQ points (95% confidence interval: 0.83, 6.56). We concluded the body of evidence was of "moderate" quality for ADHD with "limited" evidence for an association with PBDEs, based on the heterogeneity of association estimates reported by a small number of studies and the fact that chance, bias, and confounding could not be ruled out with reasonable confidence.

Conclusion: We concluded there was sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ. Preventing developmental exposure to PBDEs could help prevent loss of human intelligence. https://doi.org/10.1289/EHP1632.
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http://dx.doi.org/10.1289/EHP1632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783655PMC
August 2017

Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth: Systematic-review of the human and animal evidence.

PLoS One 2017 12;12(7):e0176331. Epub 2017 Jul 12.

Program on Reproductive Health and the Environment, University of California, San Francisco, United States of America.

Background: Adverse effects of prenatal stress or environmental chemical exposures on fetal growth are well described, yet their combined effect remains unclear.

Objectives: To conduct a systematic review on the combined impact and interaction of prenatal exposure to stress and chemicals on developmental outcomes.

Methods: We used the first three steps of the Navigation Guide systematic review. We wrote a protocol, performed a robust literature search to identify relevant animal and human studies and extracted data on developmental outcomes. For the most common outcome (fetal growth), we evaluated risk of bias, calculated effect sizes for main effects of individual and combined exposures, and performed a random effects meta-analysis of those studies reporting on odds of low birthweight (LBW) by smoking and socioeconomic status (SES).

Results: We identified 17 human- and 22 animal-studies of combined chemical and stress exposures and fetal growth. Human studies tended to have a lower risk of bias across nine domains. Generally, we found stronger effects for chemicals than stress, and these exposures were associated with reduced fetal growth in the low-stress group and the association was often greater in high stress groups, with limited evidence of effect modification. We found smoking associated with significantly increased odds of LBW, with a greater effect for high stress (low SES; OR 4.75 (2.46-9.16)) compared to low stress (high SES; OR 1.95 (95% CI 1.53-2.48)). Animal studies generally had a high risk of bias with no significant combined effect or effect modification.

Conclusions: We found that despite concern for the combined effects of environmental chemicals and stress, this is still an under-studied topic, though limited available human studies indicate chemical exposures exert stronger effects than stress, and this effect is generally larger in the presence of stress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507491PMC
September 2017

Identification of a novel locus associated with skin colour in African-admixed populations.

Sci Rep 2017 03 16;7:44548. Epub 2017 Mar 16.

Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10, rs1426654) and SLC45A2 (minimum p = 9.71 × 10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.
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http://dx.doi.org/10.1038/srep44548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353593PMC
March 2017

Breastfeeding associated with higher lung function in African American youths with asthma.

J Asthma 2017 Oct 8;54(8):856-865. Epub 2016 Dec 8.

a Department of Medicine , University of California San Francisco , San Francisco , CA , USA.

Objective: In the United States, Puerto Ricans and African Americans have lower prevalence of breastfeeding and worse clinical outcomes for asthma compared with other racial/ethnic groups. We hypothesize that the history of breastfeeding is associated with increased forced expiratory volume in 1 second (FEV) % predicted and reduced asthma exacerbations in Latino and African American youths with asthma.

Methods: As part of the Genes-environments & Admixture in Latino Americans (GALA II) Study and the Study of African Americans, asthma, Genes & Environments (SAGE II), we conducted case-only analyses in children and adolescents aged 8-21 years with asthma from four different racial/ethnic groups: African Americans (n = 426), Mexican Americans (n = 424), mixed/other Latinos (n = 255), and Puerto Ricans (n = 629). We investigated the association between any breastfeeding in infancy and FEV% predicted using multivariable linear regression; Poisson regression was used to determine the association between breastfeeding and asthma exacerbations.

Results: Prevalence of breastfeeding was lower in African Americans (59.4%) and Puerto Ricans (54.9%) compared to Mexican Americans (76.2%) and mixed/other Latinos (66.9%; p < 0.001). After adjusting for covariates, breastfeeding was associated with a 3.58% point increase in FEV% predicted (p = 0.01) and a 21% reduction in asthma exacerbations (p = 0.03) in African Americans only.

Conclusion: Breastfeeding was associated with higher FEV% predicted in asthma and reduced number of asthma exacerbations in African American youths, calling attention to continued support for breastfeeding.
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http://dx.doi.org/10.1080/02770903.2016.1266496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130885PMC
October 2017

Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies.

Chest 2017 04 1;151(4):804-812. Epub 2016 Dec 1.

Department of Medicine, University of California, San Francisco, San Francisco; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco.

Background: Asthma disproportionately affects minority populations and is associated with psychosocial stress such as racial/ethnic discrimination. We aimed to examine the association of perceived discrimination with asthma and poor asthma control in African American and Latino youth.

Methods: We included African American (n = 954), Mexican American (n = 1,086), other Latino (n = 522), and Puerto Rican Islander (n = 1,025) youth aged 8 to 21 years from the Genes-Environments and Admixture in Latino Americans study and the Study of African Americans, Asthma, Genes, and Environments. Asthma was defined by physician diagnosis, and asthma control was defined based on the National Heart, Lung, and Blood Institute guidelines. Perceived racial/ethnic discrimination was assessed by the Experiences of Discrimination questionnaire, with a focus on school, medical, and public settings. We examined the associations of perceived discrimination with each outcome and whether socioeconomic status (SES) and global African ancestry modified these associations.

Results: African American children reporting any discrimination had a 78% greater odds of experiencing asthma (OR, 1.78; 95% CI, 1.33-2.39) than did those not reporting discrimination. Similarly, African American children faced increased odds of poor asthma control with any experience of discrimination (OR, 1.97; 95% CI, 1.42-2.76) over their counterparts not reporting discrimination. These associations were not observed among Latino children. We observed heterogeneity of the association between reports of discrimination and asthma according to SES, with reports of discrimination increasing the odds of having asthma among low-SES Mexican American youth (interaction P = .01) and among high-SES other Latino youth (interaction P = .04).

Conclusions: Perceived discrimination is associated with increased odds of asthma and poorer control among African American youth. SES exacerbates the effect of perceived discrimination on having asthma among Mexican American and other Latino youth.
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http://dx.doi.org/10.1016/j.chest.2016.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472516PMC
April 2017

Association of a PAI-1 Gene Polymorphism and Early Life Infections with Asthma Risk, Exacerbations, and Reduced Lung Function.

PLoS One 2016 24;11(8):e0157848. Epub 2016 Aug 24.

Division of Allergy-Immunology, Department of Pediatrics, Northwestern University, Chicago, Illinois, United States of America.

Background: Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk.

Methods: We included Latino children, adolescents, and young adults aged 8-21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function.

Results: RSV infection (OR 9.9, 95%CI 4.9-20.2) and other LRI (OR 9.1, 95%CI 7.2-11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3-50.2) and genotype-LRI (OR 11.7, 95% CI 8.8-16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (β -2.1, 95% CI -4.0 to -0.2; β -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (β -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted.

Conclusions: A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157848PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996454PMC
July 2017

Preoperative Frailty Is Associated With Discharge to Skilled or Assisted Living Facilities After Urologic Procedures of Varying Complexity.

Urology 2016 11 5;97:25-32. Epub 2016 Jul 5.

Division of Geriatrics, University of California, San Francisco, CA.

Objective: To evaluate the association between frailty and postoperative discharge destination after different types of commonly performed urologic procedures in older patients.

Materials And Methods: Using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2011 to 2013, we identified commonly performed inpatient urologic procedures among patients aged 65 and older. We then assessed the effect of frailty, measured by the NSQIP Frailty Index (NSQIP-FI), on discharge to a skilled or assisted living facility using logistic regression and assessed the heterogeneity of this effect across procedures using 2-level random effects modeling.

Results: Overall, 1144 out of 20,794 (5.5%) urologic cases, representing 19 different procedures, resulted in discharge to a skilled or assisted living facility. Cystectomy and large transurethral resection of bladder tumor had the highest percentage (16.3%). Twenty-five percent of patients undergoing urology procedures were frail (NSQIP-FI 0.18+), including 9.8% of patients discharged to a facility. Even after adjustment for year, age, race, type of anesthesia, smoking status, recent weight loss, and whether or not the procedure was elective, frailty was strongly associated with discharge to a facility (adjusted odds ratio 3.1 [96% confidence interval 2.5, 3.8] for NSQIP-FI 0.18+ compared to NSQIP FI 0). This finding was consistent across most procedures of varying complexity with an overall effect of odds ratio 1.6 (95% confidence interval 1.5, 2.0).

Conclusion: Increasing frailty is associated with discharge to a skilled or assisted living facility across most inpatient urologic procedures evaluated, regardless of complexity. This information is important for preoperative counseling with patients undergoing urologic surgery.
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http://dx.doi.org/10.1016/j.urology.2016.03.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477056PMC
November 2016

Sensitization to mouse and cockroach allergens and asthma morbidity in urban minority youth: Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II).

Ann Allergy Asthma Immunol 2016 07 27;117(1):43-49.e1. Epub 2016 May 27.

Northwestern University Lurie Children's Hospital, Chicago, Illinois.

Background: Pest allergen sensitization is associated with asthma morbidity in urban youth but minimally explored in Latino populations. Specifically, the effect of mouse sensitization on the risk of asthma exacerbation has been unexplored in Latino subgroups.

Objective: To evaluate whether pest allergen sensitization is a predictor of asthma exacerbations and poor asthma control in urban minority children with asthma.

Methods: Latino and African American children (8-21 years old) with asthma were recruited from 4 sites across the United States. Logistic regression models evaluated the association of mouse or cockroach sensitization with asthma-related acute care visits or hospitalizations.

Results: A total of 1,992 children with asthma in the Genes-environments and Admixture in Latino American (GALA-II) and Study of African-Americans, Asthma, Genes, and Environments (SAGE-II) cohorts were studied. Asthmatic children from New York had the highest rate of pest allergen sensitization (42% mouse, 56% cockroach), with the lowest rate in San Francisco (4% mouse, 8% cockroach). Mouse sensitization, more than cockroach, was associated with increased odds of acute care visits (adjusted odds ratio [aOR], 1.47; 95% CI, 1.07-2.03) or hospitalizations (aOR, 3.07; 95% CI, 1.81-5.18), even after controlling for self-reported race and site of recruitment. In stratified analyses, Mexican youth sensitized to mouse allergen did not have higher odds of asthma exacerbation. Other Latino and Puerto Rican youth sensitized to mouse had higher odds of hospitalization for asthma (aORs, 4.57 [95% CI, 1.86-11.22] and 10.01 [95% CI, 1.77-56.6], respectively) but not emergency department visits.

Conclusion: Pest allergen sensitization is associated with a higher odds of asthma exacerbations in urban minority youth. Puerto Rican and Other Latino youth sensitized to mouse were more likely to have asthma-related hospitalizations than Mexican youth.
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http://dx.doi.org/10.1016/j.anai.2016.05.004DOI Listing
July 2016

Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan.

Environ Int 2016 Jul-Aug;92-93:716-28. Epub 2016 May 5.

University of California San Francisco, Program on Reproductive Health and the Environment, Oakland, CA, USA.

Background: There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan.

Objective: Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction?

Methods: We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data.

Results: We found 4282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: -0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: -0.38, -0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall, we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a "moderate/low" quality rating to the body of evidence for human thyroid hormone alterations and a "moderate" quality rating to the body of evidence for non-human thyroid hormone alterations.

Conclusion: Based on this application of the Navigation Guide systematic review methodology, we concluded that there was "sufficient" non-human evidence and "inadequate" human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is "possibly toxic" to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated.
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http://dx.doi.org/10.1016/j.envint.2016.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951161PMC
January 2018

Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies.

Am J Respir Crit Care Med 2016 06;193(11):1271-80

20 Centro de Neumología Pediatrica, San Juan, Puerto Rico; and.

Rationale: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking.

Objectives: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry.

Methods: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 μm and ≤2.5 μm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry.

Measurements And Main Results: A 5 μg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 μm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function.

Conclusions: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.
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http://dx.doi.org/10.1164/rccm.201508-1706OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910900PMC
June 2016

Impact of frailty on complications in patients undergoing common urological procedures: a study from the American College of Surgeons National Surgical Quality Improvement database.

BJU Int 2016 May 17;117(5):836-42. Epub 2016 Jan 17.

Division of Geriatrics, VA Medical Center, University of California, San Francisco, CA, USA.

Objectives: To evaluate the association of frailty, a measure of diminished physiological reserve, with both major and minor surgical complications among patients undergoing urological surgery.

Materials And Methods: Using data from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) from 2007 to 2013, we identified all urological cases that appeared > 1000 times in the dataset among patients aged ≥40 years. Frailty was measured using the NSQIP frailty index (FI), a validated measure that includes 11 impairments, such as decreased functional status and impaired sensorium. We created multivariable logistic regression models using the NSQIP FI to assess major and minor complications after surgery.

Results: We identified 95 108 urological cases representing 21 urological procedures. The average frequency of complications per individual was 11.7%, with the most common complications being hospital readmission (6.2%), blood transfusion (4.6%) and urinary tract infection (3.1%). Major and minor complications increased with increasing NSQIP FI. Frailty remained strongly associated with complications after adjustment for year, age, race, smoking status and method of anaesthesia (adjusted odds ratio 1.74 [95% confidence interval 1.64, 1.85] for an NSQIP FI ≥0.18). Increasing NSQIP FI was associated with increasing frequency of complications within age groups (by decade) up to age 81 years and across most procedures.

Conclusion: Frailty strongly correlates with risk of postoperative complications among patients undergoing urological surgery. This finding is true within most age groups and across most urological procedures.
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http://dx.doi.org/10.1111/bju.13399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833543PMC
May 2016

Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study.

Hepatology 2016 Feb 16;63(2):574-80. Epub 2015 Dec 16.

Department of Surgery, Division of Transplant Surgery, University of California-San Francisco, San Francisco, CA.

Unlabelled: Cirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in patients with cirrhosis awaiting liver transplantation and its association with waiting list mortality. Consecutive adults listed for liver transplantation with laboratory Model for End-Stage Liver Disease (MELD) ≥12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (0 = impaired to 12 = robust), consisting of gait, chair stands, and balance tests. Joint linear time-to-event analyses modeled the simultaneous impact of the longitudinal trajectory of physical function on waiting list mortality (=death or delisted for being too sick for liver transplantation). Included were 309 liver transplantation candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% had hepatic encephalopathy, and 83% were Child class B or C. At a median follow-up of 14 months, 15% died or were delisted and 28% underwent liver transplantation. Average physical function worsened per 3 months on the waiting list: -0.38 kg in grip strength, -0.05 meters/second in gait, 0.03 seconds in chair stands, and -0.16 Short Physical Performance Battery points. In joint models of longitudinal trajectories of physical function and waiting list mortality adjusted for MELD-Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with waiting list mortality: grip (hazard ratio = 0.89, 95% confidence interval 0.83-0.95), gait (hazard ratio = 0.72, 95% confidence interval 0.62-0.84), chair stands (hazard ratio = 1.17, 95% confidence interval 1.09-1.25), and Short Physical Performance Battery <10 (hazard ratio = 1.45, 95% confidence interval 1.15-2.20).

Conclusion: Liver transplantation candidates experience significant functional decline on the waiting list, despite modest wait time and low baseline MELD; decline in physical function is associated with an increased risk of death or delisting, independent of liver disease severity.
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http://dx.doi.org/10.1002/hep.28316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718851PMC
February 2016

Identification and Correction of Sample Mix-Ups in Expression Genetic Data: A Case Study.

G3 (Bethesda) 2015 Aug 19;5(10):2177-86. Epub 2015 Aug 19.

Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.

In a mouse intercross with more than 500 animals and genome-wide gene expression data on six tissues, we identified a high proportion (18%) of sample mix-ups in the genotype data. Local expression quantitative trait loci (eQTL; genetic loci influencing gene expression) with extremely large effect were used to form a classifier to predict an individual's eQTL genotype based on expression data alone. By considering multiple eQTL and their related transcripts, we identified numerous individuals whose predicted eQTL genotypes (based on their expression data) did not match their observed genotypes, and then went on to identify other individuals whose genotypes did match the predicted eQTL genotypes. The concordance of predictions across six tissues indicated that the problem was due to mix-ups in the genotypes (although we further identified a small number of sample mix-ups in each of the six panels of gene expression microarrays). Consideration of the plate positions of the DNA samples indicated a number of off-by-one and off-by-two errors, likely the result of pipetting errors. Such sample mix-ups can be a problem in any genetic study, but eQTL data allow us to identify, and even correct, such problems. Our methods have been implemented in an R package, R/lineup.
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http://dx.doi.org/10.1534/g3.115.019778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592999PMC
August 2015

Exploiting Differential Gene Expression and Epistasis to Discover Candidate Genes for Drought-Associated QTLs in Arabidopsis thaliana.

Plant Cell 2015 Apr 14;27(4):969-83. Epub 2015 Apr 14.

Department of BioAgricultural Sciences and Pest Management, Colorado State University, Fort Collins, Colorado 80523.

Soil water availability represents one of the most important selective agents for plants in nature and the single greatest abiotic determinant of agricultural productivity, yet the genetic bases of drought acclimation responses remain poorly understood. Here, we developed a systems-genetic approach to characterize quantitative trait loci (QTLs), physiological traits and genes that affect responses to soil moisture deficit in the TSUxKAS mapping population of Arabidopsis thaliana. To determine the effects of candidate genes underlying QTLs, we analyzed gene expression as a covariate within the QTL model in an effort to mechanistically link markers, RNA expression, and the phenotype. This strategy produced ranked lists of candidate genes for several drought-associated traits, including water use efficiency, growth, abscisic acid concentration (ABA), and proline concentration. As a proof of concept, we recovered known causal loci for several QTLs. For other traits, including ABA, we identified novel loci not previously associated with drought. Furthermore, we documented natural variation at two key steps in proline metabolism and demonstrated that the mitochondrial genome differentially affects genomic QTLs to influence proline accumulation. These findings demonstrate that linking genome, transcriptome, and phenotype data holds great promise to extend the utility of genetic mapping, even when QTL effects are modest or complex.
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http://dx.doi.org/10.1105/tpc.15.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558705PMC
April 2015

Obesity and bronchodilator response in black and Hispanic children and adolescents with asthma.

Chest 2015 Jun;147(6):1591-1598

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA; Department of Medicine, University of California, San Francisco, CA.

Background: Obesity is associated with poor asthma control, increased asthma morbidity, and decreased response to inhaled corticosteroids. We hypothesized that obesity would be associated with decreased bronchodilator responsiveness in children and adolescents with asthma. In addition, we hypothesized that subjects who were obese and unresponsive to bronchodilator would have worse asthma control and would require more asthma controller medications.

Methods: In the Study of African Americans, Asthma, Genes, and Environments (SAGE II) and the Genes-environments and Admixture in Latino Americans (GALA II) study, two identical, parallel, case-control studies of asthma, we examined the association between obesity and bronchodilator response in 2,963 black and Latino subjects enrolled from 2008 to 2013 using multivariable logistic regression. Using bronchodilator responsiveness, we compared asthma symptoms, controller medication usage, and asthma exacerbations between nonobese (< 95th% BMI) and obese (≥ 95th% BMI) subjects.

Results: The odds of being bronchodilator unresponsive were 24% (OR, 1.24; 95% CI, 1.03-1.49) higher among obese children and adolescents compared with their not obese counterparts after adjustment for age, race/ethnicity, sex, recruitment site, baseline lung function (FEV1/FVC), and controller medication. Bronchodilator-unresponsive obese subjects were more likely to report wheezing (OR, 1.38; 95% CI, 1.13-1.70), being awakened at night (OR, 1.34; 95% CI, 1.09-1.65), using leukotriene receptor inhibitors (OR, 1.33; 95% CI, 1.05-1.70), and using inhaled corticosteroid with long-acting β2-agonist (OR, 1.37; 95% CI, 1.05-1.78) than were their nonobese counterpart. These associations were not seen in the bronchodilator-responsive group.

Conclusions: Obesity is associated with bronchodilator unresponsiveness among black and Latino children and adolescents with asthma. The findings on obesity and bronchodilator unresponsiveness represent a unique opportunity to identify factors affecting asthma control in blacks and Latinos.
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http://dx.doi.org/10.1378/chest.14-2689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451713PMC
June 2015