Estimating the burden of disease attributable to ambient air pollution (ambient PM2.5 and ambient ozone) in South Africa for 2000, 2006 and 2012.

Background: Globally, a growing body of research has shown that ambient air pollution is one of the most critical environmental issues, especially in relation to human health. Exposure to ambient air pollution leads to serious health conditions such as lower respiratory infections, cancers, diabetes mellitus type 2, ischaemic heart disease, stroke and chronic obstructive pulmonary disease. Objectives: To estimate the burden of disease attributable to ambient air pollution in South Africa (SA) for the years 2000, 2006 and 2012. Methods: Comparative risk assessment method was used to determine the burden of disease due to two pollutants (particulate matter (PM2.5) and ambient ozone). Regionally optimised fully coupled climate chemistry models and surface air pollution observations were used to generate concentrations of PM2.5 and ozone for each SA Census Small Area Level, for the year 2012. For 2000 and 2006, population-weighted PM2.5and ozone were estimated, based on the 2012 results. Following the identification of disease outcomes associated with particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and ozone exposure, the attributable burden of disease was estimated for 2000, 2006 and 2012. Furthermore, for the year 2012, the burden of disease attributable to ambient air pollution exposure was computed at provincial levels. Results: In 2012, approximately 97.6% of people in SA were exposed to PM2.5 at levels above the 2005 World Health Organization guideline: 10 µg/m3 annual mean. From 2000 to 2012, population-weighted annual average PM2.5 increased from 26.6 µg/m3 to 29.7 µg/m3, and ozone 6-month high 8-hour daily maximum increased from 64.4 parts per billion (ppb) to 72.1 ppb. At a national scale, in the year 2000, 15 619 (95% uncertainty interval (UI) 8 958 - 21 849) deaths were attributed to PM2.5 exposure, while 1 326 (95% UI 534 - 1 885) deaths were attributed to ozone. In 2006, an estimated 19 672 deaths (95% UI 11 526 - 27 086) were attributed to PM2.5, and a further 1 591 deaths (95% UI 651 - 2 236) to ozone exposure. In 2012, deaths attributed to PM2.5 were 19 507 (95% UI 11 318 - 27 111), and to ozone 1 734 (95% UI 727 - 2 399). Additionally, population-weighted provincial scale analysis showed that Gauteng Province had the highest number of attributable deaths due to both PM2.5 and ozone in 2012. Conclusion: The study showed that ambient air pollution exposure is an important health risk in SA, requiring both short- and long-term intervention. In the short term, the SA Ambient Air Quality Standards and industrial minimum emissions standards need to be enforced. In the longer term, to reduce air pollution and the associated disease burden, the combustion of fossil fuels as a source of energy for power generation and transportation, as well as industrial and domestic uses, needs to be replaced with clean renewable energy sources. In addition to local measures, when the southern African prevalent anticyclonic air dynamics that transport regionally emitted pollutants into SA (especially from biomass burning) are considered, it is also advisable to establish long-term regional co-operation in reducing air pollution.

High-dose strategies for managing phosphine-resistant populations of Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae).

BACKGROUND: Rhyzopertha dominica is a serious pest of stored grains and many populations have resistance to the fumigant phosphine. Some populations contain beetles with a 'strong resistance' phenotype. Recent work found the LC50 values for two strong-resistant populations recently studied in North America, Belle Glade and Minneapolis were 100- and 595-fold higher, respectively, compared to LC50 of a lab-susceptible strain. Populations with 'weak-resistant' phenotypes had LC50 values 5- to 10-fold that of a susceptible strain. The work reported below aimed to determine the minimum phosphine concentrations and number of days of exposure needed to effectively control all life stages of representative weak- and strong-resistant strains, and then to recommend the treatment conditions needed to control strongly phosphine-resistant R. dominica in pest populations. RESULTS: A dose-mortality assay estimated that phosphine fumigation over 48 h using 730-870 ppm at 25° C would control adults of both strongly resistant R. dominica populations. Fumigations with mixed life stage cultures found 200 ppm killed all susceptible and weak-resistant beetles in 2 days, but the strong-resistant Minneapolis and Belle Glade strains had substantial survivors at 200 ppm. Furthermore, the Belle Glade strain had beetles that survived 1000 ppm in 2-day fumigations. The strong-resistant Belle Glade strain needed nearly 10 days at over 400 ppm to have acceptable levels of control. CONCLUSION: This study recommends protocols to manage strongly resistant R. dominica populations provided that a minimum phosphine concentration of 400 ppm be maintained at 25° C or higher for up to 10 days. © 2019 Society of Chemical Industry.

Relation between body composition at birth and child development at 2 years of age: a prospective cohort study among Ethiopian children.

BACKGROUND/OBJECTIVES: Birth weight (BW), independent of socioeconomic status, has been identified as a predictor for childhood cognitive development. However, it is not known whether this relation is related to low BW per se or particularly related to a deficit in fat mass (FM) or fat-free mass (FFM) at birth. This study therefore aimed at investigating the relation between body composition at birth and child development at 2 years of age. SUBJECTS/METHODS: An Ethiopian birth cohort was followed up at 2 years. Body composition was measured within 48 h of birth using infant air-displacement plethysmography. Child development was assessed at 2 years of age using Denver developmental screening test. Associations between body composition at birth and development at 2 years of age were tested using linear regression analysis. RESULTS: FFM but not FM at birth was positively associated with higher global developmental score at 2 years of age (ß=2.48, 95% confidence interval (CI) 0.17; 4.79) adjusted for neonatal, postnatal and parental characteristics. This association was attributable to the association with the language developmental domain (ß=1.61, 95 CI 0.33; 2.90). CONCLUSIONS: Among Ethiopian children, FFM at birth but not FM predicted better global and language development at 2 years of age. Higher FFM at birth might have exerted a positive effect on the growth and differentiation of the brain and neuronal circuits for better development. This study therefore highlights the need to improve mother's nutritional status during pregnancy in ways that stimulate fetal FFM growth.

Evaluation of Real-Time Mortality Surveillance Based on Media Reports.

OBJECTIVE: We evaluated the usefulness and accuracy of media-reported data for active disaster-related mortality surveillance. METHODS: From October 29 through November 5, 2012, epidemiologists from the Centers for Disease Control and Prevention (CDC) tracked online media reports for Hurricane Sandy-related deaths by use of a keyword search. To evaluate the media-reported data, vital statistics records of Sandy-related deaths were compared to corresponding media-reported deaths and assessed for percentage match. Sensitivity, positive predictive value (PPV), and timeliness of the media reports for detecting Sandy-related deaths were calculated. RESULTS: Ninety-nine media-reported deaths were identified and compared with the 90 vital statistics death records sent to the CDC by New York City (NYC) and the 5 states that agreed to participate in this study. Seventy-five (76%) of the media reports matched with vital statistics records. Only NYC was able to actively track Sandy-related deaths during the event. Moderate sensitivity (83%) and PPV (83%) were calculated for the matching media-reported deaths for NYC. CONCLUSIONS: During Hurricane Sandy, the media-reported information was moderately sensitive, and percentage match with vital statistics records was also moderate. The results indicate that online media-reported deaths can be useful as a supplemental source of information for situational awareness and immediate public health decision-making during the initial response stage of a disaster. (Disaster Med Public Health Preparedness. 2017;11:460-466).

Use of Community Assessments for Public Health Emergency Response (CASPERs) to Rapidly Assess Public Health Issues - United States, 2003-2012.

INTRODUCTION: Community Assessment for Public Health Emergency Response (CASPER) is an epidemiologic technique designed to provide quick, inexpensive, accurate, and reliable household-based public health information about a community's emergency response needs. The Health Studies Branch at the Centers for Disease Control and Prevention (CDC) provides in-field assistance and technical support to state, local, tribal, and territorial (SLTT) health departments in conducting CASPERs during a disaster response and in non-emergency settings. Data from CASPERs conducted from 2003 through 2012 were reviewed to describe uses of CASPER, ascertain strengths of the CASPER methodology, and highlight significant findings. METHODS: Through an assessment of the CDC's CASPER metadatabase, all CASPERs that involved CDC support performed in US states and territories from 2003 through 2012 were reviewed and compared descriptively for differences in geographic distribution, sampling methodology, mapping tool, assessment settings, and result and action taken by decision makers. RESULTS: For the study period, 53 CASPERs were conducted in 13 states and one US territory. Among the 53 CASPERS, 38 (71.6%) used the traditional 2-stage cluster sampling methodology, 10 (18.8%) used a 3-stage cluster sampling, and two (3.7%) used a simple random sampling methodology. Among the CASPERs, 37 (69.9%) were conducted in response to specific natural or human-induced disasters, including 14 (37.8%) for hurricanes. The remaining 16 (30.1%) CASPERS were conducted in non-disaster settings to assess household preparedness levels or potential effects of a proposed plan or program. The most common recommendations resulting from a disaster-related CASPER were to educate the community on available resources (27; 72.9%) and provide services (18; 48.6%) such as debris removals and refills of medications. In preparedness CASPERs, the most common recommendations were to educate the community in disaster preparedness (5; 31.2%) and to revise or improve preparedness plans (5; 31.2%). Twenty-five (47.1%) CASPERs documented on the report or publications the public health action has taken based on the result or recommendations. Findings from 27 (50.9%) of the CASPERs conducted with CDC assistance were published in peer-reviewed journals or elsewhere. CONCLUSION: The number of CASPERs conducted with CDC assistance has increased and diversified over the past decade. The CASPERs' results and recommendations supported the public health decisions that benefitted the community. Overall, the findings suggest that the CASPER is a useful tool for collecting household-level disaster preparedness and response data and generating information to support public health action.

Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients.

OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS containing whey (LNS/w), an LNS containing soy (LNS/s) or no LNS. Trough plasma concentrations of efavirenz and nevirapine were measured at 1 and 2 months. Genotyping for 516 G>T and 983 T>C polymorphisms of the cytochrome P450 (CYP) 2B6 locus was performed. Multilevel linear mixed-effects models were used to assess the associations between LNS and plasma efavirenz and nevirapine concentrations. RESULTS: In patients with BMI > 17 kg/m(2), nevirapine concentrations were lower in the LNS/w and LNS/s groups by a median of -2.3 µg/mL [interquartile range (IQR) -3.9; -0.9 µg/mL; P = 0.002] and -2.1 µg/mL (IQR -3.9; -0.9 µg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 µg/mL higher plasma efavirenz concentration compared with the wild type (P < 0.0001), while it was not associated with plasma nevirapine concentrations. CONCLUSIONS: Intake of an LNS was associated with lower plasma nevirapine trough concentrations, indicating possible drug-LNS interactions. The clinical relevance of such reductions in nevirapine exposure is not clear. Plasma efavirenz concentration was not affected by the LNS.

Physical activity and capacity at initiation of antiretroviral treatment in HIV patients in Ethiopia.

SUMMARY We described levels of habitual physical activity and physical capacity in HIV patients initiating antiretroviral treatment in Ethiopia and assessed the role of HIV and nutritional indicators on these outcomes. Physical activity energy expenditure (PAEE) and activity levels were measured with combined heart rate and movement sensors. Physical capacity was assessed by grip strength, sleeping heart rate and heart rate economy. Grip strength data was also available from a sex- and age-matched HIV-negative reference group. Median PAEE was 27.9 (interquartile range 17.4-39.8) kJ/kg per day and mean ± s.d. grip strength was 23.6 ± 6.7 kg. Advanced HIV disease predicted reduced levels of both physical activity and capacity; e.g. each unit viral load [log(1+copies/ml)] was associated with -15% PAEE (P < 0.001) and -1.0 kg grip strength (P < 0.001). Grip strength was 4.2 kg lower in patients compared to HIV-negative individuals (P < 0.001). Low body mass index (BMI) predicted poor physical activity and capacity independently of HIV status, e.g. BMI <16 was associated with -42% PAEE (P < 0.001) and -6.8 kg grip strength (P < 0.001) compared to BMI ≥18.5. The study shows that advanced HIV and malnutrition are associated with considerably lower levels of physical activity and capacity in patients at initiation of antiretroviral treatment.

Assessing radiation emergency preparedness planning by using community assessment for public health emergency response (CASPER) methodology.

INTRODUCTION: Approximately 1.2 million persons in Oakland County, Michigan (USA) reside less than 50 miles from the Fermi Nuclear Power Plant, Unit 2, but information is limited regarding how residents might react during a radiation emergency. Community Assessment for Public Health Emergency Response (CASPER) survey methodology has been used in disaster and non disaster settings to collect reliable and accurate population-based public health information, but it has not been used to assess household-level emergency preparedness for a radiation emergency. To improve emergency preparedness plans in Oakland County, including how residents might respond during a radiation emergency, Oakland County Health Division (OCHD), with assistance from the Centers for Disease Control and Prevention (CDC) and the Michigan Department of Community Health (MDCH), conducted a CASPER survey. METHODS: During September 2012, a 2-stage cluster sampling design was used to select 210 representative households in Oakland County. By using in-person surveys, the proportion of households with essential needs and supplies, how residents might respond to public health authorities' instructions, and their main source for obtaining information during a radiation emergency were assessed. Data were weighted to account for the complex sampling design. RESULTS: Of the goal of 210 households, 192 (91.4%) surveys were completed: 64.7% and 85.4% of respondents indicated having 3-day supplies of water and of non perishable food, respectively; 62.8% had a 7-day supply of prescription medication for each person who needed it. Additionally, 64.2% had a working carbon monoxide detector; 67.1% had a first-aid kit; and 52% had an alternative heat source. In response to instructions from public health officials during a radiation emergency, 93.3% of all respondents would report to a radiation screening center; 96% would evacuate; and 91.8% would shelter-in-place. During a radiation emergency, 55.8% of respondents indicated their main information source would be television, 18.4% radio, and 13.6% the Internet. The most trusted source for information would be the local public health department (36.5%), local news (23%), a physician (11.2%), and family members (11.1%). Including completed and incomplete interviews, refusals, and non respondents, 517 total households were contacted. CONCLUSIONS: CASPER data regarding how residents might react during a radiation emergency provided objective and quantifiable information that will be used to develop Oakland County's radiation emergency preparedness plans. Survey information demonstrates the feasibility and usefulness of CASPER methodology for radiation emergency preparedness planning.

Intermolecular interactions and the thermodynamic properties of supercritical fluids.

The role of different contributions to intermolecular interactions on the thermodynamic properties of supercritical fluids is investigated. Molecular dynamics simulation results are reported for the energy, pressure, thermal pressure coefficient, thermal expansion coefficient, isothermal and adiabatic compressibilities, isobaric and isochoric heat capacities, Joule-Thomson coefficient, and speed of sound of fluids interacting via both the Lennard-Jones and Weeks-Chandler-Andersen potentials. These properties were obtained for a wide range of temperatures, pressures, and densities. For each thermodynamic property, an excess value is determined to distinguish between attraction and repulsion. It is found that the contributions of intermolecular interactions have varying effects depending on the thermodynamic property. The maxima exhibited by the isochoric and isobaric heat capacities, isothermal compressibilities, and thermal expansion coefficient are attributed to interactions in the Lennard-Jones well. Repulsion is required to obtain physically realistic speeds of sound and both repulsion and attraction are necessary to observe a Joule-Thomson inversion curve. Significantly, both maxima and minima are observed for the isobaric and isochoric heat capacities of the supercritical Lennard-Jones fluid. It is postulated that the loci of these maxima and minima converge to a common point via the same power law relationship as the phase coexistence curve with an exponent of ß = 0.32. This provides an explanation for the terminal isobaric heat capacity maximum in supercritical fluids.

Thermodynamic properties of liquid water from a polarizable intermolecular potential.

Molecular dynamics simulation results are reported for the pressure, isothermal pressure coefficient, thermal expansion coefficient, isothermal and adiabatic compressibilities, isobaric and isochoric heat capacities, Joule-Thomson coefficient and speed of sound of liquid water using a polarizable potential [Li et al., J. Chem. Phys. 127, 154509 (2007)]. These properties were obtained for a wide range of temperatures and pressures at a common liquid density using the treatment of Lustig [J. Chem. Phys. 100, 3048 (1994)] and Meier and Kabelac [J. Chem. Phys. 124, 064104 (2006)], whereby thermodynamic state variables are expressible in terms of phase-space functions determined directly from molecular dynamics simulations. Comparison with experimental data indicates that the polarizable potential can be used to predict most thermodynamic properties with a very good degree of accuracy.

Quantitative characterization of changes in the cardiac mitochondrial proteome during anesthetic preconditioning and ischemia.

Changes in mitochondrial bioenergetics have been proposed to be critical for triggering and effecting anesthetic-induced preconditioning (APC) against cardiac ischemia and reperfusion injury. The objective of this study was to analyze changes in mitochondrial protein levels and link those changes to potential functional changes. A (18)O-labeling method was applied for relative comparison of cardiac mitochondrial samples from control and isoflurane exposed rats before and after ischemia and reperfusion. Wistar rats were exposed to isoflurane for 30 min (APC) or did not receive the anesthetic (control). Rats were subjected to 30 min coronary occlusion and 15 min reperfusion without (ischemia) or after APC (ischemia + APC). The following comparisons were made: control vs. APC, control vs. ischemia, and APC vs. ischemia + APC. Proteins were analyzed by liquid chromatography-mass spectrometry. A total of 98 proteins currently annotated as mitochondrial proteins in the UniProt database were positively identified from three replicate experiments. Most of the changes during APC and ischemia occur in complexes of the electron transport chain. Overall, fewer changes in ETC complexes were found when comparing APC with APC + ischemia than when comparing control and ischemia. This corresponds to the preservation of bioenergetics due to APC after ischemia and reperfusion as indicated by preserved ATP level and generation. APC itself induced changes in complex I, but those changes were not correlated with activity changes in mitochondria after APC. Thus, a proteomic mass spectral approach does not only assess quantitative changes without prior knowledge of proteins, but also allows insight into the mechanisms of ischemia and reperfusion injury and APC.

A brief report of surveillance of traumatic experiences and exposures after the earthquake-tsunami in American Samoa, 2009.

CONTEXT: Rapid mental health surveillance during the acute phase of a disaster response can inform the allocation of limited clinical resources and provide essential household-level risk estimates for recovery planning. OBJECTIVE: To describe the use of the PsySTART Rapid Mental Health Triage and Incident Management System for individual-level clinical triage and traumatic exposure assessment in the aftermath of a large-scale disaster. METHODS: We conducted a cross-sectional, comparative review of mental health triage data collected with the PsySTART system from survivors of the September 2009 earthquake-tsunami in American Samoa. Data were obtained from two sources--secondary triage of patients and a standardized community assessment survey-and analyzed descriptively. The main outcome measures were survivor-reported traumatic experiences and exposures--called triage factors--associated with risk for developing severe distress and new mental health disorders following disasters. RESULTS: The most common triage factors reported by survivors referred for mental health services were "felt extreme panic/fear" (93%) and "felt direct threat to life" (93%). The most common factor reported by persons in tsunami-affected communities was "felt extreme panic or fear" (75%). Proportions of severe triage factors reported by persons living in the community were consistently lower than those reported by patients referred for mental health services. CONCLUSIONS: The combination of evidence-based mental health triage and community assessment gave hospital-based providers, local public health officials, and federal response teams a strategy to match limited clinical resources with survivors at greatest risk. Also, it produced a common operating picture of acute and chronic mental health needs among disaster systems of care operating in American Samoa.

Evaluation of active mortality surveillance system data for monitoring hurricane-related deaths-Texas, 2008.

INTRODUCTION: The Texas Department of State Health Services (DSHS) implemented an active mortality surveillance system to enumerate and characterize hurricane-related deaths during Hurricane Ike in 2008. This surveillance system used established guidelines and case definitions to categorize deaths as directly, indirectly, and possibly related to Hurricane Ike. OBJECTIVE: The objective of this study was to evaluate Texas DSHS' active mortality surveillance system using US Centers for Disease Control and Prevention's (CDC) surveillance system evaluation guidelines. METHODS: Using CDC's Updated Guidelines for Surveillance System Evaluation, the active mortality surveillance system of the Texas DSHS was evaluated. Data from the active mortality surveillance system were compared with Texas vital statistics data for the same time period to estimate the completeness of reported disaster-related deaths. RESULTS: From September 8 through October 13, 2008, medical examiners (MEs) and Justices of the Peace (JPs) in 44 affected counties reported deaths daily by using a one-page, standardized mortality form. The active mortality surveillance system identified 74 hurricane-related deaths, whereas a review of vital statistics data revealed only four deaths that were hurricane-related. The average time of reporting a death by active mortality surveillance and vital statistics was 14 days and 16 days, respectively. CONCLUSIONS: Texas's active mortality surveillance system successfully identified hurricane-related deaths. Evaluation of the active mortality surveillance system suggested that it is necessary to collect detailed and representative mortality data during a hurricane because vital statistics do not capture sufficient information to identify whether deaths are hurricane-related. The results from this evaluation will help improve active mortality surveillance during hurricanes which, in turn, will enhance preparedness and response plans and identify public health interventions to reduce future hurricane-related mortality rates.

AncestrySNPminer: a bioinformatics tool to retrieve and develop ancestry informative SNP panels.

A wealth of genomic information is available in public and private databases. However, this information is underutilized for uncovering population specific and functionally relevant markers underlying complex human traits. Given the huge amount of SNP data available from the annotation of human genetic variation, data mining is a faster and cost effective approach for investigating the number of SNPs that are informative for ancestry. In this study, we present AncestrySNPminer, the first web-based bioinformatics tool specifically designed to retrieve Ancestry Informative Markers (AIMs) from genomic data sets and link these informative markers to genes and ontological annotation classes. The tool includes an automated and simple "scripting at the click of a button" functionality that enables researchers to perform various population genomics statistical analyses methods with user friendly querying and filtering of data sets across various populations through a single web interface. AncestrySNPminer can be freely accessed at https://research.cchmc.org/mershalab/AncestrySNPminer/login.php.

Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma.

RATIONALE AND OBJECTIVE: Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated. METHODS: Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP. MEASUREMENTS AND MAIN RESULTS: We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls. CONCLUSION: Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.

Individualized risk for statin-induced myopathy: current knowledge, emerging challenges and potential solutions.

Skeletal muscle toxicity is the primary adverse effect of statins. In this review, we summarize current knowledge regarding the genetic and nongenetic determinants of risk for statin induced myopathy. Many genetic factors were initially identified through candidate gene association studies limited to pharmacokinetic (PK) targets. Through genome-wide association studies, it has become clear that SLCO1B1 is among the strongest PK predictors of myopathy risk. Genome-wide association studies have also expanded our understanding of pharmacodynamic candidate genes, including RYR2. It is anticipated that deep resequencing efforts will define new loci with rare variants that also contribute, and sophisticated computational approaches will be needed to characterize gene-gene and gene-environment interactions. Beyond environment, race is a critical covariate, and its influence is only partly explained by geographic differences in the frequency of known pharmacodynamic and PK variants. As such, admixture analyses will be essential for a full understanding of statin-induced myopathy.

Comparison of measures of marker informativeness for ancestry and admixture mapping.

BACKGROUND: Admixture mapping is a powerful gene mapping approach for an admixed population formed from ancestral populations with different allele frequencies. The power of this method relies on the ability of ancestry informative markers (AIMs) to infer ancestry along the chromosomes of admixed individuals. In this study, more than one million SNPs from HapMap databases and simulated data have been interrogated in admixed populations using various measures of ancestry informativeness: Fisher Information Content (FIC), Shannon Information Content (SIC), F statistics (FST), Informativeness for Assignment Measure (In), and the Absolute Allele Frequency Differences (delta, δ). The objectives are to compare these measures of informativeness to select SNP markers for ancestry inference, and to determine the accuracy of AIM panels selected by each measure in estimating the contributions of the ancestors to the admixed population. RESULTS: FST and In had the highest Spearman correlation and the best agreement as measured by Kappa statistics based on deciles. Although the different measures of marker informativeness performed comparably well, analyses based on the top 1 to 10% ranked informative markers of simulated data showed that In was better in estimating ancestry for an admixed population. CONCLUSIONS: Although millions of SNPs have been identified, only a small subset needs to be genotyped in order to accurately predict ancestry with a minimal error rate in a cost-effective manner. In this article, we compared various methods for selecting ancestry informative SNPs using simulations as well as SNP genotype data from samples of admixed populations and showed that the In measure estimates ancestry proportion (in an admixed population) with lower bias and mean square error.

Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.

BACKGROUND: Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes. METHODOLOGY/PRINCIPAL FINDINGS: Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.

Inter-chromosomal variation in the pattern of human population genetic structure.

Emerging technologies now make it possible to genotype hundreds of thousands of genetic variations in individuals, across the genome. The study of loci at finer scales will facilitate the understanding of genetic variation at genomic and geographic levels. We examined global and chromosomal variations across HapMap populations using 3.7 million single nucleotide polymorphisms to search for the most stratified genomic regions of human populations and linked these regions to ontological annotation and functional network analysis. To achieve this, we used five complementary statistical and genetic network procedures: principal component (PC), cluster, discriminant, fixation index (FST) and network/pathway analyses. At the global level, the first two PC scores were sufficient to account for major population structure; however, chromosomal level analysis detected subtle forms of population structure within continental populations, and as many as 31 PCs were required to classify individuals into homogeneous groups. Using recommended population ancestry differentiation measures, a total of 126 regions of the genome were catalogued. Gene ontology and networks analyses revealed that these regions included the genes encoding oculocutaneous albinism II (OCA2), hect domain and RLD 2 (HERC2), ectodysplasin A receptor (EDAR) and solute carrier family 45, member 2 (SLC45A2). These genes are associated with melanin production, which is involved in the development of skin and hair colour, skin cancer and eye pigmentation. We also identified the genes encoding interferon-γ (IFNG) and death-associated protein kinase 1 (DAPK1), which are associated with cell death, inflammatory and immunological diseases. An in-depth understanding of these genomic regions may help to explain variations in adaptation to different environments. Our approach offers a comprehensive strategy for analysing chromosome-based population structure and differentiation, and demonstrates the application of complementary statistical and functional network analysis in human genetic variation studies.

Genotype-environment interactions and their translational implications.

Organisms frequently encounter different environmental conditions. The physiological and behavioral responses to these conditions depend on the genetic make up of individuals. Genotype generally remains constant from one environment to another, although occasional spontaneous mutations may occur which cause it to change. However, when the same genotype is subjected to different environments, it can produce a wide range of phenotypes. These phenotypic variations are attributable to the effect of the environment on the expression and function of genes influencing the trait. Changes in the relative performance of genotypes across different environments are referred to as genotype-environment interactions (GEI). A general argument for research on the impact of GEI in common diseases is that it provides insights into disease processes at the population, individual and molecular levels. In humans, GEI is complicated by multiple factors including phenocopies, genocopies, epigenetics and imprinting. A better understanding of GEI is essential if patients are to make informed health choices guided by their genomic information. In this article, we clarify the role of the environment on phenotype, we describe how human population structure can obscure the resolution of GEI and we discuss how emerging biobanks across the globe can be coordinated to further our understanding of genotype-phenotype associations within the context of varying environment.