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Most clinical research in the United States has been carried out in atypical populations. This study, done in a network of primary care populations in Virginia, calculates the denominator by the utilization correction factor method and compares the demography with that of the population of the state. The demographic characteristics of the patients in the network are very similar to those of the underlying populations and on the same order of state-of-the-art sampling methods in current use. [ABSTRACT FROM PUBLISHER]

Rising incidence of waterborne diseases including Legionellosis linked to low chlorine residuals in buildings and the availability of inexpensive testing options, create an opportunity for citizen science chorine monitoring to complement sampling done by water utilities. University researchers and Flint residents coordinated a citizen science chlorine surveillance campaign in Flint, Michigan in 2015-19, that helped expose the nature of two deadly Legionnaires Disease outbreaks in 2014-2015 during the Flint Water Crisis and progress of system recovery during the Federal emergency. Results obtained with an inexpensive color wheel were in agreement with a digital colorimeter (R 2 =0.99; p = 2.81 × 10 -21 ) at 15 sites geographically distributed across Flint. Blinded tests revealed good agreement between official (n = 2051) and citizen (n = 654) data in terms of determining whether regulatory guidelines for chlorine were met, but a discovery that the citizen data were statistically lower than the city's (p<0.00001) especially in warm summer months led to recommendations for increased flushing of service lines before measurements. This work suggests that expanded citizen surveillance of chlorine, site specific flushing advice, and guidance on decisions about water heater set point could help consumers reduce Legionella risks in their homes. Citizen science initiatives for chlorine monitoring offer a unique opportunity for mutually beneficial collaborations between consumers and utilities to reduce the main source of waterborne disease in developed countries., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Inhaled corticosteroids (ICSs) are considered the most effective anti-inflammatory therapy for asthma control and management; however, there is substantial treatment response variability., Objective: We sought to identify genetic markers of ICS response by conducting the largest pharmacogenetic investigation to date in 2672 ICS-treated patients with asthma., Methods: Genotyping and imputation was performed in fluticasone furoate (FF) or fluticasone propionate-treated patients with asthma from 3 phase IIB and 4 phase IIIA randomized, double-blind, placebo-controlled, parallel group, multicenter studies. The primary end point analyzed was change in trough FEV 1 (ΔFEV 1 ) from baseline to 8 to 12 weeks of treatment., Results: More than 9.8 million common genetic variants (minor allele frequency ≥ 1%) were analyzed to test for association with ΔFEV 1 . No genetic variant met the prespecified threshold for statistical significance., Conclusions: This study provides no evidence to confirm previously reported associations between candidate genetic variants and ICS response (ΔFEV 1 ) in patients with asthma. In addition, no variant satisfied the criterion for genome-wide significance in our study. Common genetic variants are therefore unlikely to prove useful as predictive biomarkers of ICS response in patients with asthma., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Pharmacokinetic variability in drug exposure is a concern for all compounds in development including those for the treatment of asthma and other respiratory disorders. Substantial variability in the oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor that attenuates the production of leukotriene B4 and cysteinyl leukotrienes, is largely unaccounted for by clinical variables. A study of 41 patients, 78% (32/41) of whom were non-Hispanic whites, with mild to moderate asthma identified an association of UGT1A1*28 and UGT1A3*2 with the oral clearance of GSK2190915 (P=3.8×10⁻⁴ and 1.2×10⁻⁵, respectively). However, in a subsequent replication study of 403 non-Hispanic white patients with asthma, we failed to observe a statistically significant association between oral clearance of GSK2190915 and either UGT1A1*28 or UGT1A3*2 (P>0.05). Therefore, genetic effects that could explain the systemic exposure level variability of GSK2190915 were not identified.

Purpose: Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects., Methods: The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated., Results: The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively., Conclusions: Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.

Background: The collection of viable DNA samples is an essential element of any genetics research programme. Biological samples for DNA purification are now routinely collected in many studies with a variety of sampling methods available. Initial observation in this study suggested a reduced genotyping success rate of some saliva derived DNA samples when compared to blood derived DNA samples prompting further investigation., Methods: Genotyping success rate was investigated to assess the suitability of using saliva samples in future safety and efficacy pharmacogenetics experiments. The Oragene® OG-300 DNA Self-Collection kit was used to collect and extract DNA from saliva from 1468 subjects enrolled in global clinical studies. Statistical analysis evaluated the impact of saliva sample volume of collection on the quality, yield, concentration and performance of saliva DNA in genotyping assays., Results: Across 13 global clinical studies that utilized the Oragene® OG-300 DNA Self-Collection kit there was variability in the volume of saliva sample collection with ~31% of participants providing 0.5 mL of saliva, rather than the recommended 2 mL. While the majority of saliva DNA samples provided high quality genotype data, collection of 0.5 mL volumes of saliva contributed to DNA samples being significantly less likely to pass genotyping quality control standards. Assessment of DNA sample characteristics that may influence genotyping outcomes indicated that saliva sample volume, DNA purity and turbidity were independently associated with sample genotype pass rate, but that saliva collection volume had the greatest effect., Conclusion: When employing saliva sampling to obtain DNA, it is important to encourage all study participants to provide sufficient sample to minimize potential loss of data in downstream genotyping experiments.

Background: Identifying genetic markers of susceptibility to exacerbations may improve patient management, decrease morbidity, and lead to drug development., Objectives: To assess whether genetic markers associated with severe asthma exacerbations in previous reports are associated with less severe events that do not require intensive care and intubation and to identify additional markers in candidate genes and throughout the genome., Methods: A total of 199 patients and 502 controls (individuals without an exacerbation) were identified from 4 clinical trials. We genotyped 51 markers from 17 genes previously reported to be associated with exacerbations; a whole genome scan was used to identify additional markers. Admixture analysis was conducted to characterize the presence of ancestral groups. The genetic marker effects were assessed by logistic regression for each study followed by a meta-analysis., Results: Several coding variants in the IL4R gene had a genetic effect across 3 studies, including rs1805011 in IL4R (P < .0006). In addition, 3 markers in the IFNB1 gene showed evidence of association (P < .002) but only in the study with African Americans. Because these markers did not meet the prespecified multiplicity-adjusted significance level of P = .0002, we were unable to confirm previously published results for less severe events. The whole genome scan identified genes related to mast cell mediator release. The admixture analysis suggests that ancestry was best characterized by the presence of 3 ancestral groups., Conclusion: We were unable to confirm previously reported associations of genetic markers with asthma exacerbations. Although, in general, the patients studied had less severe asthma than patients in earlier reports, these results suggest involvement of similar pathways., Trial Registration: clinicaltrials.gov Identifiers: NTC00452699, NCT00452348, NTC00102765, NCT00843193., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR)., Methods: DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR., Results: The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants., Conclusion: The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount., (© 2010 Blackwell Publishing Ltd.)

Abacavir hypersensitivity (ABC HSR) is a treatment-limiting adverse event associated with the use of the antiretroviral medicine, abacavir. The objective of the ABC HSR pharmacogenetics program was to identify clinically useful genetic risk factors to predict an individual patient's risk for ABC HSR. The major histocompatibility complex allele, HLA-B*5701, was identified retrospectively and confirmed with independent sample sets. The clinical utility of prospective HLA-B*5701 screening was demonstrated in a blinded randomized clinical trial and in open-label cohorts. Screening has been incorporated into clinical practice and the ABC HSR pharmacogenetics program has been highlighted as a success by pharmacogenetics researchers. Important lessons from this pharmacogenetics program will be discussed in this paper.

Background: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis., Methods: White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants., Results: Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%., Conclusions: Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are highly effective in the treatment of type 2 diabetes. In some patients, PPARgamma ligands are associated with fluid retention/oedema, for which the mechanism is not fully understood. A pharmacogenetic study was undertaken to investigate effects of variations in 21 candidate genes related to epithelial sodium channel (ENaC) pathways on oedema. This study used DNA samples collected from type 2 diabetes phase III clinical trials of the PPARgamma agonist farglitazar (administered alone or in combination with insulin or glyburide) and investigated oedema reported as an adverse event as phenotype. Initial case-control analysis of oedema identified candidate gene single nucleotide polymorphisms with significant associations. These included three polymorphisms in ENaCbeta subunit (SCNN1B) that showed significant associations (P<0.05) with the two combination treatments in discrete regions of the gene, but not farglitazar treatment alone. Sequencing of SCNN1B in 207 Caucasian participants receiving farglitazar plus insulin or glyburide combination therapies, identified additional polymorphisms that were also significantly associated with oedema (P<0.0005) and maintained the treatment-regional associations. Further covariate analysis accounting for clinical factors influencing oedema supported these observations. One of the SCNN1B polymorphisms, at position -405 of the 5' flanking region (rs34241435), was predicted to modify transcriptional interactions and in a transfected COS cell luciferase reporter gene assay exhibited higher promoter activity. These exploratory studies provide clinical pharmacogenetic and functional genomic evidence to support a pivotal role for ENaC regulation in PPARgamma-induced oedema and provide insight into mechanisms and possible management of this side effect.

Abacavir is an effective antiretroviral drug used to treat HIV-1 infection. Approximately 5% of patients treated with abacavir develop a hypersensitivity reaction that requires discontinuation of the drug. In an initial pharmacogenetic study conducted in a predominantly White male population, multiple markers in the human leukocyte antigen (HLA)-B chromosomal region were associated with hypersensitivity to abacavir. The HLA-B*5701 association has now been confirmed in White males in a subsequent, larger study (n=293, p=4.7 x 10(-18)) and is also observed in White females (n=56, p=6.8 x 10(-6)) and Hispanics (n=104, p=2.1 x 10(-4)). HLA-B*5701 was not associated with hypersensitivity in Blacks (n=78, p=0.27). HLA-B*5701 alone lacks sufficient predictive value to identify patients at risk for hypersensitivity to abacavir across diverse patient populations. Efforts are ongoing to identify markers with sufficient sensitivity and specificity to be clinically useful. Even after a marker set is identified, appropriate clinical identification and management of hypersensitivity to abacavir must remain the cornerstone of clinical practice.

Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.

The Genetics Directorate was established at Glaxo Wellcome (GW) in 1997. The goals of the Directorate are to identify susceptibility genes for common diseases with large unmet therapeutic need, apply genetic methods for the targeted development of medicines so that the right medicine is developed for the right patient, assist in translating gene discoveries into target selection, and represent genetics accurately internally within GW and externally (to laypersons, the medical community, the business community, government representatives, and regulatory agencies). As part of the goal of developing the right medication for the right patient, GW has added genetic research to its clinical drug studies in every major therapeutic area. GW worked closely with international ethicists experienced in the area of genetic research to develop the process and documents that are currently in use; these undergo frequent, rigorous review in light of the changing regulatory and legal environment and the needs of clinical investigators and patients. The addition of genetic research to clinical studies was accompanied by significant education efforts within GW and for study-site personnel, ethics committees, and regulatory authorities. Feedback from all those involved is an integral part of implementing GW's genetic research and is used to fine-tune the processes and protocol and consent document templates. A recently completed review of the approval rate from ethics committees in several countries has revealed trends in EC/IRB (Ethics Committees/Institutional Review Boards) questions and concerns about genetic research. This article will focus on the lessons learned from incorporating genetic research into clinical studies at over 1,500 international sites and will include summaries of the feedback from investigators, EC/IRBs, and regulatory authorities. It also will include a discussion of the potential applications of SNP (single nucleotide polymorphism) map technologies to pharmacogenetics by increasing the ability to correlate patients' genetic information with their response to medicines.

We investigated the relative contributions of genetic, individual environmental, and shared environmental effects on 2,3-diphosphoglycerate (DPG) regulation in preadolescent children. In a population of 165 early pubescent boy and girl twin pairs (11.4 y old), of whom 63 were passive smokers, we asked: 1) Are there differences in the control of DPG levels between early pubertal boys and girls? 2) If present, are these differences influenced by exposure to passive cigarette smoke? Non-passive-smoking boys and girls had similar DPG levels. With exposure to passive smoke, DPG levels increased in boys (p = 0.02) but not in girls. Analysis of variance on DPG demonstrated a parental smoking effect (p = 0.008) and suggested an interactive effect between parental smoking and sex of the child (p = 0.08). Univariate genetic analyses suggested that genes operated at different magnitudes in boys (9%) and girls (39%) in explaining a significant portion of the variance in DPG. The magnitude of shared environmental influences was greater in boys (62%) than in girls (34%), whereas individual environmental effects were similar in boys (29%) and girls (26%). Early pubertal boys differ from girls in their regulation of DPG. Environmental stressors such as passive cigarette smoke may elicit different responses in males and females, even at an early age. The use of path analysis may provide important insights into the mechanisms and interactions of genetic and environmental effects that underly the childhood antecedents of atherosclerotic heart disease.

Left ventricular (LV) hypertrophy in adults is a recognized risk factor for the subsequent development of cardiovascular morbidity. To make informed preventive health decisions it is important to understand the interaction of genes and environment on LV mass. In both children and adults, weight is a strong correlate of LV mass. We hypothesized that genetic influences common to both of these variables could in part explain the strong relation between weight and LV mass in children. In a population of 341 twins (11 years old), these questions were asked: (1) How much of the total variance of LV mass is under genetic control? (2) After accounting for weight and weight adjusted for sexual maturity, how much of the remaining variance is genetic? (3) Of the total genetic variance, what proportion is specific for LV mass and what proportion is common to both weight and LV mass? (4) How much of the correlation between these 2 variables is explained by genes common to both LV mass and weight? Univariate genetic analyses documented that genes operating at different magnitudes in boys (63%) and girls (71%) explain a significant proportion of the variance of LV mass. After removing the effect of weight and sexual maturity by regression methods, genes remain an important influence. Bivariate genetic analyses confirmed that genes common to LV mass and weight significantly influence the covariation of these variables and that greater than 90% of the correlation of LV mass and weight is due to common genes.

We conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of lipoprotein cholesterol and its subfractions in children during early adolescence. Univariate path analysis was used to determine the relative contributions of genes, individual environment, and family environment to these measures in 233 11-year-old Caucasian twin pairs. For high density lipoprotein, high density lipoprotein2, low density lipoprotein, very low density lipoprotein, and triglycerides, a model that incorporated genes and individual environmental variation but not common environment was sufficient to explain the variation. Different magnitudes of genetic effects were seen for total cholesterol in boys and girls. High density lipoprotein3 showed different magnitudes by sex for genetic and individual environmental effect. Intermediate density lipoprotein was the only cholesterol subfraction in which shared, or common, environment was found to make a statistically significant contribution to the variation.

We investigated whether left ventricular (LV) structural or functional abnormalities persist in children on long-term follow-up after successful correction of coarctation of the aorta. Two-dimensional directed M-mode and Doppler echocardiographic examinations were performed in 11 such subjects and 22 age-matched control subjects. Digitized tracings were made from M-mode recordings of the LV and Doppler mitral valve inflow recordings to measure septal, posterior wall, and LV dimensions, LV mass, shortening fraction, peak shortening and lengthening velocities, diastolic filling time, peak E velocity, peak A velocity, and velocity time integrals. Despite group similarities in age, body size, and systolic blood pressure, greater fractional shortening (p = 0.0001), indexed peak shortening velocity (p less than 0.001), and greater LV mass index (p less than 0.05) were seen in the coarctation group in the face of lower LV wall stress (p = 0.0001). LV mass index correlated with the resting arm-leg gradient, which ranged from -4 to +10 mm Hg. The coarctation group had decreased early filling (p less than 0.006) with compensatory increased late diastolic filling (p less than 0.05). Diastolic filling abnormalities were prominent in the older coarctation subjects and were related to both systolic blood pressure (p less than 0.001) and LV mass index (p less than 0.01). Despite apparently successful repair of coarctation of the aorta, persistent alterations in both systolic and diastolic LV function and LV mass are present in children at long-term follow-up, which are related to the resting arm-leg gradient.(ABSTRACT TRUNCATED AT 250 WORDS)

We have conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of anthropometric measurements in children during early adolescence. Univariate path analysis was used to estimate the relative contributions of genes, individual environment, and family environment to measures of childhood obesity in 259 11-y-old Caucasian twin pairs. Triceps, subcapular, and suprailiac skinfold thicknesses, as well as waist circumferences, ht, and wt were measured in a standardized protocol. In this sample, a parsimonious model that included only additive genetic effects and environmental factors unique to the individual provided an adequate explanation for the variation in ht, wt, quetelet index, and subscapular and triceps skinfolds. In this largely preadolescent population, different magnitudes of genetic effects were seen in males and females for waist circumference, biiliac diameter, and suprailiac skinfold.

Aortic stiffness, the maximal frequency shift in the descending aorta divided by the Doppler acceleration time, was studied in 384 eleven year old twin children. The extent to which this measurement provided a prediction of systolic blood pressure that was independent of body size, heart rate, cardiac contractility and left ventricular mass was investigated. Aortic stiffness, after adjustment for height and weight, correlated significantly with systolic blood pressure (r = 0.22, p less than 0.01), but not with diastolic blood pressure. The short- (r = 0.82) and longer- (r = 0.68) term reproducibility of aortic stiffness was high. This measure appears to be a more powerful predictor of systolic blood pressure than is left ventricular mass. Aortic stiffness is a highly reproducible Doppler variable that may explain in part the contribution of the aortic wall elastic properties to the level of systolic blood pressure in preadolescent children at rest.