Thiazides and β-blockers cause adverse metabolic effects (AMEs), but whether these effects share predictors with blood pressure (BP) response is unknown. We aimed to determine whether AMEs are correlated with BP response in uncomplicated hypertensives.
In a multicenter, open-label, parallel-group trial, we enrolled 569 persons, aged 17–65, with random assignment to 9 weeks of daily hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by 9 weeks of add-on therapy with the alternate agent. Measurements included home BP, averaged over 1 week, weight and fasting levels of serum glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and uric acid (UA) before and after monotherapy and after add-on therapy.
Increases in UA correlated with reductions in systolic BP (SBP) (r = −0.18; P = 0.003) and diastolic BP (DBP) (r = −0.20; P = 0.001) following HCTZ monotherapy and add-on therapy (r = −0.27 and r = −0.21, respectively; both P < 0.001). After adjustment for age, race, gender, and baseline body mass index (BMI), only the correlation between UA and DBP response became nonsignificant. Reductions in HDL correlated with systolic response following atenolol monotherapy (r = 0.18; P = 0.002) and with systolic and diastolic response following add-on therapy (r = 0.30 and r = 0.24, respectively; both P < 0.0001). These correlations remained significant after covariate adjustment. BP responses were not correlated with changes in glucose, LDL, triglycerides, or weight following either therapy.
BP response correlated with changes in UA following HCTZ therapy and HDL following atenolol therapy. No other significant correlations were observed between BP response and AMEs, suggesting that these effects generally do not share predictors. Patients should be monitored for AMEs, regardless of BP response.
thiazide diuretics; atenolol; β-blockers; blood pressure; hydrochlorothiazide; hypertension; metabolic effects
In the past few decades, consumption of added sugars has increased dramatically. Studies have linked high sugar intake with increased risk for a number of diseases. Importantly, fructose, a component of sugar, has been linked with the development of features of metabolic syndrome. This study determined if single nucleotide polymorphisms in genes involved in fructose transport (solute carrier family 2 facilitated glucose transporter, member 2 (SLC2A2) and solute carrier family 2 facilitated glucose/fructose transporter, member 5 (SLC2A5)) and metabolism (ketohexokinase (KHK)) affect inter-individual variability in metabolic phenotypes, such as increased serum uric acid levels.
The influence of SLC2A2, SLC2A5, and KHK SNPs on metabolic phenotypes was tested in 237 European Americans and 167 African Americans from the Pharmacogenomic Evaluation and Antihypertensive Responses (PEAR) study. Using baseline untreated fasting data, associations were considered significant if p≤0.005. These SNPs were then evaluated for potential replication (p≤0.05) using data from the Genetic Epidemiology of Responses to Antihypertensives (GERA) studies.
SLC2A5 rs5438 was associated with an increase in serum uric acid in European American males. However, we were unable to replicate the association in GERA. The minor allele of SLC2A2 rs8192675 showed an association with lower high-density lipoproteins in European Americans (A/A: 51.0 mg/dL, A/G: 47.0 mg/dL, G/G: 41.5 mg/dL, p = 0.0034) in PEAR. The association between rs8192675 and lower high-density lipoproteins was replicated in the combined European American GERA study samples (A/A: 47.6 mg/dL, A/G: 48.6 mg/dL, G/G: 41.9 mg/dL, p = 0.0315).
The association between SLC2A2 rs8192675 and high-density lipoproteins suggests the polymorphism may play a role in influencing high-density lipoproteins and thus metabolic risk of cardiovascular disease.
Recently, the high-mobility group A1 gene (HMGA1) variant IVS5-13insC has been associated with type 2 diabetes, but reported associations are inconsistent and data are lacking in Hispanic and African American populations. We sought to investigate the HMGA1-diabetes association and to characterize IVS5-13insC allele frequencies and linkage disequilibrium (LD) in 3,070 Caucasian, Hispanic, and African American patients from the INternational VErapamil SR-Trandolapril STudy (INVEST).
INVEST was a randomized, multicenter trial comparing two antihypertensive treatment strategies in an ethnically diverse cohort of hypertensive, coronary artery disease patients. Controls, who were diabetes-free throughout the study, and type 2 diabetes cases, either prevalent or incident, were genotyped for IVS5-13insC using Taqman®, confirmed with Pyrosequencing and Sanger sequencing. For LD analysis, genotyping for eight additional HMGA1 single nucleotide polymorphisms (SNPs) was performed using the Illumina® HumanCVD BeadChip. We used logistic regression to test association of the HMGA1 IVS5-13insC and diabetes, adjusted for age, gender, body mass index, and percentage European, African, and Native American ancestry.
We observed IVS5-13insC minor allele frequencies consistent with previous literature in Caucasians and African Americans (0.03 in cases and 0.04 in controls for both race/ethnic groups), and higher frequencies in Hispanics (0.07 in cases and 0.07 in controls). The IVS5-13insC was not associated with type 2 diabetes overall (odds ratio 0.98 [0.76-1.26], p=0.88) or in any race/ethnic group. Pairwise LD (r2) of IVS5-13insC and rs9394200, a SNP previously used as a tag SNP for IVS5-13insC, was low (r2=0.47 in Caucasians, r2=0.25 in Hispanics, and r2=0.06 in African Americans). Furthermore, in silico analysis suggested a lack of functional consequences for the IVS5-13insC variant.
Our results suggest that IVS5-13insC is not a functional variant and not associated with type 2 diabetes in an ethnically diverse, hypertensive, coronary artery disease population. Larger, more adequately powered studies need to be performed to confirm our findings.
HMGA1; Type 2 diabetes; Genetics
The detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a160 kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3 kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5 hours to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus.
pattern recognition; next-generation sequencing analysis; indels; rare variants; FKBP5; HLA
Patients vary in their responses to drug therapy, and some of that variability is genetically-determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented: cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and anti-platelet agents. A brief view of potential pathways to implementation is presented.
genetics; pharmacogenetics; pharmacogenomics; drug therapy
Due to time-dependent confounding by blood pressure and differential loss to follow-up, it is difficult to estimate the effectiveness of aggressive versus conventional antihypertensive combination therapies in non-randomized comparisons.
We utilized data from 22,576 hypertensive coronary artery disease patients, prospectively enrolled in the INternational VErapamil-Trandolapril STudy (INVEST). Our post-hoc analyses did not consider the randomized treatment strategies, but instead defined exposure time-dependently as aggressive treatment (≥3 concomitantly used antihypertensive medications) versus conventional treatment (≤2 concomitantly used antihypertensive medications). Study outcome was defined as time to first serious cardiovascular event (non-fatal myocardial infarction, non-fatal stroke, or all-cause death). We compared hazard ratio (HR) estimates for aggressive vs. conventional treatment from a Marginal Structural Cox Model (MSCM) to estimates from a standard Cox model. Both models included exposure to antihypertensive treatment at each follow-up visit, demographics, and baseline cardiovascular risk factors, including blood pressure. The MSCM further adjusted for systolic blood pressure at each follow-up visit, through inverse probability of treatment weights.
2,269 (10.1%) patients experienced a cardiovascular event over a total follow-up of 60,939 person-years. The HR for aggressive treatment estimated by the standard Cox model was 0.96 (95% confidence interval 0.87-1.07). The equivalent MSCM, which was able to account for changes in systolic blood pressure during follow-up, estimated a HR of 0.81 (95% CI 0.71-0.92).
Using a MSCM, aggressive treatment was associated with a lower risk for serious cardiovascular outcomes compared to conventional treatment. In contrast, a standard Cox model estimated similar risks for aggressive and conventional treatments.
Clinicaltrials.gov Identifier: NCT00133692
Blood pressure; Hypertension; Time-dependent confounding; Marginal structural models
Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product . Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes.
We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition.
The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein truncating mutations. Haplotype analysis using short tandem repeat microsatellite markers did not indicate the presence of a haplotype around PPARGC1A which segregated with disease in the family.
The application of the GINI method to LCLs to identify transcripts harbouring germline truncating mutations is challenging due to a number of factors related to cell type, microarray sensitivity and variations in NMD efficiency.
Heart failure is an increasingly common disease associated with significant morbidity and mortality in the aging population. Recent advances in heart failure pharmacotherapy have established a number of agents as beneficial to disease progression and outcomes. However, current consensus guideline recommended pharmacotherapy may not represent an optimal treatment strategy in all heart failure patients. Specifically, individuals with genetic variation in regions central to mediation of beneficial response to standard heart failure agents may not receive optimal benefit from these drugs. Additionally, targeted approaches in Phase III clinical trials that select patients for inclusion based on the genotype most likely to respond might advance the currently stalled drug development pipeline in heart failure. This article reviews the literature in heart failure pharmacogenetics to date, opportunities for discovery in recent and upcoming clinical trials, as well as future directions in this field.
heart failure; pharmacogenetics; left ventricular ejection fraction; β-blocker; ACE inhibitor; mortality
Liver X receptor-α (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene have been previously associated with metabolic phenotypes (dyslipidemia and elevated BMI). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in INVEST-GENES, a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease.
Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159 and rs10501321. 1059 subjects were genotyped from the INVEST-GENES case-control set (Verapamil-SR or Atenolol based treatment strategies), comprised of 297 cases frequency matched approximately 2.5:1 with event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal MI, or nonfatal stroke. Adjusted odds ratios (OR) were calculated using logistic regression.
Three of the seven SNPs were associated with significant effects on the primary outcome in Non-Blacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome (OR: 0.62, CI: 0.45-0.85, P=0.003 and OR: 0.60, CI: 0.39-0.91, P=0.016 respectively). The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03-1.95, P=0.03). Furthermore, there was a significant genotype-treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for Verapamil SR strategy compared to Atenolol: 2.86, CI: 1.50-5.46, P=0.0015). Diplotype analyses revealed that the SNPs are rarely co-inherited and support the directionally opposite effects of the SNPs on the primary outcome.
LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest LXRA is a genetic/pharmacogenetic target that should be further explored.
LXRA; Nuclear Receptor; Pharmacogenetics; Polymorphisms; Cardiovascular Disease; Hypertension; Atenolol; Verapamil
While numerous SNPs in Chromosome 9p21 have been associated with coronary artery disease (CAD) and incident MI in Caucasians, there are limited and conflicting reports on the association of this locus with prognosis in Caucasians with existing CAD and no reports in blacks or Hispanics. We investigated the hypothesis that 9p21 polymorphisms are associated with increased risk for adverse cardiovascular outcomes in patients with documented CAD.
Methods and Results
We studied the association of 155 chromosome 9p21 SNPs with adverse outcomes among hypertensive CAD patients of multiple races/ethnicities in INVEST GENES (the INternational VErapamil SR Trandolapril STudy GENetic Substudy, n= 1,460, n = 5,979 for 2 SNPs) and with replication testing of 4 SNPs in the INFORM (INvestigation oF Outcomes from acute coronary syndRoMe; n=714) study of acute coronary syndrome (ACS) patients. In INVEST, the haplotype comprised of the risk allele for the widely reported 9p21 SNPs was associated with better prognosis in Caucasians (OR, 95% CI: 0.72, 0.57–0.92, p = 0.0085) but not blacks (1.21, 0.68–1.24, p = 0.52) or Hispanics (0.96, 0.65–1.44, p=0.86). A less commonly reported LD block was associated with worse prognosis in INVEST among both Caucasians (OR=1.52 (1.20–1.93), p = 0.0006) and African Americans (OR = 4.11 (1.55–10.88), p = 0.004).
Our findings suggest previously reported chromosome 9p21 SNPs, which predict incident CAD, are not associated with higher risk for adverse outcomes in patients with established CAD. The less commonly reported LD block warrants further investigation.
chromosome 9p21; cardiovascular outcomes; genetic polymorphisms; INVEST; INFORM
Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.
We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant.
In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.
Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.
Pharmacogenomics; Pharmacogenetics; hydrochlorothiazide; hypertension; blood pressure; DOT1L; SIRT1; MLLT3; SGK1; histone methylation
To determine whether office, home, ambulatory daytime and nighttime blood pressure (BP) responses to antihypertensive drug therapy measure the same signal and which method provides greatest power to identify genetic predictors of BP response.
We analyzed office, home, ambulatory daytime and nighttime BP responses in hypertensive adults randomized to atenolol (N = 242) or hydrochlorothiazide (N = 257) in the Pharmacogenomic Evaluation of Antihypertensive Responses Study. Since different measured BP responses may have different predictors, we tested the "same signal" model by using linear regression methods to determine whether known predictors of BP response depend on the method of BP measurement. We estimated signal-to-noise ratios and compared power to identify a genetic polymorphism predicting BP response measured by each method separately and by weighted averages of multiple methods.
After adjustment for pretreatment BP level, known predictors of BP response including plasma renin activity, race, and sex were independent of the method of BP measurement. Signal-to-noise ratios were more than 2-fold greater for home and ambulatory daytime BP responses than for office and ambulatory nighttime BP responses and up to 11-fold greater for weighted averages of all four methods. Power to identify a genetic polymorphism predicting BP response was directly related to the signal-to-noise ratio and, therefore, greatest with the weighted averages.
Since different methods of measuring BP response to antihypertensive drug therapy measure the same signal, weighted averages of the BP responses measured by multiple methods minimize measurement error and optimize power to identify genetic predictors of BP response.
hypertension; blood pressure monitoring; antihypertensive drug therapy; beta-blocker; thiazide diuretic; plasma renin activity
Polymorphisms in and around the Cholesteryl Ester Transfer Protein (CETP) gene have been associated with HDL levels, risk for coronary artery disease (CAD), and response to therapy. The mechanism of action of these polymorphisms has yet to be defined. We used mRNA allelic expression and splice isoform measurements in human liver tissues to identify the genetic variants affecting CETP levels. Allelic CETP mRNA expression ratios in 56 human livers were strongly associated with several variants 2.5–7 kb upstream of the transcription start site (e.g., rs247616 p = 6.4×10−5, allele frequency 33%). In addition, a common alternatively spliced CETP isoform lacking exon 9 (Δ9), has been shown to prevent CETP secretion in a dominant-negative manner. The Δ 9 expression ranged from 10 to 48% of total CETP mRNA in 94 livers. Increased formation of this isoform was exclusively associated with an exon 9 polymorphism rs5883-C>T (p = 6.8×10−10) and intron 8 polymorphism rs9930761-T>C (5.6×10−8) (in high linkage disequilibrium with allele frequencies 6–7%). rs9930761 changes a key splicing branch point nucleotide in intron 8, while rs5883 alters an exonic splicing enhancer sequence in exon 9.
The effect of these polymorphisms was evaluated in two clinical studies. In the Whitehall II study of 4745 subjects, both rs247616 and rs5883T/rs9930761C were independently associated with increased HDL-C levels in males with similar effect size (rs247616 p = 9.6×10−28 and rs5883 p = 8.6×10−10, adjusted for rs247616). In an independent multiethnic US cohort of hypertensive subjects with CAD (INVEST-GENE), rs5883T/rs9930761C alone were significantly associated with increased incidence of MI, stroke, and all-cause mortality in males (rs5883: OR 2.36 (CI 1.29–4.30), p = 0.005, n = 866). These variants did not reach significance in females in either study. Similar to earlier results linking low CETP activity with poor outcomes in males, our results suggest genetic, sex-dependent CETP splicing effects on cardiovascular risk by a mechanism independent of circulating HDL-C levels.
Background and objective
Warfarin is a commonly used oral anticoagulant with a narrow therapeutic index and various genetic and clinical factors that influence interpatient variability in dose requirements. This study investigated the impact of genetic and nongenetic factors on warfarin dose requirements in Egyptians.
DNA was extracted from 207 patients taking warfarin for more than 2 months and genotyped for VKORC1 (3673 G> A), CYP2C9 *2*3*4*5*8, CYP4F2 (V33M; rs2108622), APOE (rs429358, rs7412), and CALU (rs339097) gene polymorphisms. Linear regression modeling was conducted to identify the genetic and nongenetic factors that independently influence warfarin dose requirements.
VKORC1 3673 AA or GA genotype (P < 0.0001), one or two variant alleles of CYP2C9 gene (P= 0.0004), APOE ε2 haplotype (P = 0.01), and increasing age (P < 0.0001) were all associated with lower warfarin dose, whereas smoking (P = 0.025) and pulmonary embolism (P = 0.0059) showed association with higher warfarin doses. These factors explained 31% of the warfarin dose variability. This is the first independent confirmation of the association of the CALU rs339097 variant with higher warfarin dose requirement, although inclusion of this single nucleotide polymorphism in the multiple regression model failed to achieve significance (P = 0.066). CYP4F2 (V33M) polymorphism was not significant (P = 0.314), despite its high frequency in the studied population (42%).
The study shows that VKORC1, CYP2C9 polymorphisms, APOE ε2 variant, and several clinical/ demographic variables are important determinants of warfarin dose requirements in Egyptian patients. The percentage of variability explained by these factors is lower than in those of European ancestry, but similar to the variability explained in Asians and African ancestry.
APOE; CALU; CYP2C9; CYP4F2; Egyptian; polymorphism; warfarin; VKORC1
Coping Effectively with Heart Failure (COPE-HF) is an ongoing randomized clinical trial funded by the National Institutes of Health to evaluate if a Coping Skills Training (CST) intervention will result in improved health status and quality of life as well as reduced mortality and hospitalizations compared to a Heart Failure Education (HFE) intervention.
Two hundred heart failure (HF) patients recruited from Duke University Medical Center and the University of North Carolina Hospital systems will be randomized to a CST intervention (16 weekly, 30 minute telephone counselling sessions including motivational interviewing and individually tailored cognitive behavioral therapy) or to an HFE intervention (16 weekly, 30 minute telephone sessions including education and symptom monitoring). Primary outcomes will include post-intervention effects on HF biomarkers (B-Type naturetic peptide, ejection fraction) and quality of life, as well as long-term clinical outcomes (hospitalizations and death). Secondary analyses will include an evaluation of treatment effects across subpopulations, and potential mechanisms by which CST may improve clinical outcomes.
COPE-HF is a proof-of-concept study that should provide important insights into the health benefits of a CST intervention designed to enhance HF self-management, improve health behaviors, and reduce psychological distress.
Self-management; biomarkers; quality of life; depression
Although sustainability is a key component in the evaluation of continuous quality improvement (CQI) projects, medicine resident CQI projects are often evaluated by immediate improvements in targeted areas without addressing sustainability.
To assess the sustainability of resident CQI projects in an ambulatory university-based clinic.
During their ambulatory rotation, all second year internal medicine residents use the American Board of Internal Medicine’s Clinical Preventive Services (CPS) Practice Improvement Modules (PIM) to complete chart reviews, patient surveys, and a system survey. The residents then develop a group CQI project and collect early post data. Third year residents return to evaluate their original CQI project during an ambulatory rotation two to six months later and complete four plan-do-study-act (PDSA) cycles on each CQI project.
From July 2006 to June 2009, 64 (100%) medicine residents completed the CQI curriculum. Residents completed six group projects and examined their success using early (2 to 6 weeks) and late (2 to 6 months) post-intervention data. Three of the projects demonstrated sustainable improvement in the resident continuity clinic.
When residents are taught principles of sustainability and spread and asked to complete multiple PDSA cycles, they are able to identify common themes that may contribute to success of QI projects over time.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1547-y) contains supplementary material, which is available to authorized users.
resident education; quality improvement; sustainability; practice-based learning and improvement; system-based practice
The G-protein coupled receptor kinases GRK2 and GRK5 are important regulators of beta-adrenergic signaling. This study characterized single nucleotide polymorphisms in the GRK2 gene (ADRBK1)and determined if these and a GRK5 Gln41Leu polymorphism affect the blood pressure (BP)response to atenolol or hydrochlorothiazide or adverse cardiovascular outcomes in hypertensives.
ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were tested for mRNA expression differences in 96 lymphoblastoid cell line samples and 12 leukocyte samples from hypertensives. BP response to atenolol and hydrochlorothiazide by ADRBK1 SNPs and GRK5 Gln41Leuwas tested in 418patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leuon death, myocardial infarction or stroke in treated hypertensive patients was evaluated in a case-control cohort (1:3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy (INVEST GENES) using logistic regression models.
A novel ADRBK1 promoter SNP was not associated with differential GRK2 expression. GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes independent of treatment strategy(adjusted odds ratio 0.535, 95% confidence interval 0.313 – 0.951, P = 0.0222)but was not associated with BP response to antihypertensive medication. An ADRBK1 SNP (rs1894111G>A) showed a signal for association with systolic and diastolic BP(SBP, DBP) response to hydrochlorothiazide in whites(DBP: −11.29±3.74 mmHg (G/A) vs. −4.26±4.79 mmHg (G/G), P = 0.0034 and SBP: −18.37±14.90 mmHg (G/A), −8.11±7.55 mmHg (G/G), P = 0.0191).
The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.
GRK5; GRK2; ADRBK1; polymorphism; hypertension; beta-blocker; atenolol; diuretic; hydrochlorothiazide
Polymorphisms (SNPs) within the regulatory β2 subunit of the voltage-gated calcium channel (CACNB2) may contribute to variable treatment response to antihypertensive drugs and adverse cardiovascular outcomes.
Methods and Results
SNPs in CACNB2 from 60 ethnically diverse individuals were identified and characterized. Three common SNPs (rs2357928, rs7069292 and rs61839258) and a GWAS identified intronic SNP (rs11014166) were genotyped for a clinical association study in 5,598 hypertensive patients with coronary artery disease randomized to a beta-blocker (BB) or a calcium channel blocker (CCB) treatment strategy in INVEST-GENES. Reporter gene assays were conducted on the promoter SNP showing association with clinical outcomes. Twenty-one novel SNPs were identified. A promoter A>G SNP (rs2357928) was found to have significant interaction with treatment strategy for adverse cardiovascular outcomes (p for interaction = 0.002). In Caucasians, rs2357928 GG patients randomized to CCB were more likely to experience adverse outcome than those randomized to BB treatment strategy, with adjusted hazard ratio (CCB vs. BB) of 2.35 (1.19-4.66), p = 0.014. There was no evidence for such treatment difference in AG (1.16, 0.75-1.79, p = 0.69) and AA individuals (0.63, 0.36-1.11, p = 0.11). This finding was consistent in Hispanics and African Americans. CACNB2 rs11014166 showed similar pharmacogenetic effect in Hispanics, but not in Caucasians or African Americans. Reporter assay analysis of rs2357928 showed a significant increase in promoter activity for the G allele compared to the A allele.
These data suggest genetic variation within CACNB2 may influence treatment related outcomes in high risk hypertensive patients.
Clinical Trial Registration Information
Clinical trial identifier: NCT00133692, URL: http://clinicaltrials.gov/ct/gui/show/NCT00133692).
Genetic variations; CACNB2; hypertension; cardiovascular outcomes; INVEST-GENES
Improving patients' ability to identify their inpatient physicians and understand their roles is vital to safe patient care. We designed picture cards to facilitate physician introductions. We assessed the effect of Feedback Care and Evaluation (FACE™) cards on patient: (1) ability to correctly identify their inpatient physicians, and (2) understanding of their roles.
In October 2006, team members introduced themselves with FACE™ cards, which included a photo and an explanation of their roles. During an inpatient interview research assistants asked patients to name their inpatient physicians and trainees, and rate their understanding of their physicians' roles.
1686 (80%) patients in the baseline period and 857 (67%) in the intervention period participated in the evaluation. With the FACE™ intervention, patients were significantly more likely to correctly identify at least one inpatient physician (attending, resident, or intern) [baseline 12.5% vs. intervention 21.1%; p<0.001]. Of the 181 patients who were able to correctly identify at least one inpatient physician in the intervention period, research assistants noted that 59% (n=107) had FACE™ cards visible in their rooms. Surprisingly, fewer patients rated their understanding of their physicians' roles as excellent or very good in the intervention period (45.6%) compared to the baseline period (55.3%) (p<0.001).
Although FACE™ cards improved patients' ability to identify their inpatient physicians, many patients still cannot identify their inpatient doctors. The FACE™ cards also served to highlight patients' misunderstanding of their physicians' roles.
identification; physician communication; role understanding
Case-crossover studies used to investigate associations between an environmental exposure and an acute health response, such as stroke, will often use the day an individual presents to an emergency department (ED) or is admitted to hospital to infer when the stroke occurred. Similarly, they will use patient's place of residence to assign exposure. The validity of using these two data elements, typically extracted from administrative databases or patient charts, to define the time of stroke onset and to assign exposure are critical in this field of research as air pollutant concentrations are temporally and spatially variable. Our a priori hypotheses were that date of presentation differs from the date of stroke onset for a substantial number of patients, and that assigning exposure to ambient pollution using place of residence introduces an important source of exposure measurement error. The objective of this study was to improve our understanding on how these sources of errors influence risk estimates derived using a case-crossover study design.
We sought to collect survey data from stroke patients presenting to hospital EDs in Edmonton, Canada on the date, time, location and nature of activities at onset of stroke symptoms. The daily mean ambient concentrations of NO2 and PM2.5 on the self-reported day of stroke onset was estimated from continuous fixed-site monitoring stations.
Of the 336 participating patients, 241 were able to recall when their stroke started and 72.6% (95% confidence interval [CI]: 66.9 - 78.3%) experienced stroke onset the same day they presented to the ED. For subjects whose day of stroke onset differed from the day of presentation to the ED, this difference ranged from 1 to 12 days (mean = 1.8; median = 1). In these subjects, there were no systematic differences in assigned pollution levels for either NO2 or PM2.5 when day of presentation rather than day of stroke onset was used. At the time of stroke onset, 89.9% (95% CI: 86.6 - 93.1%) reported that they were inside, while 84.5% (95% CI: 80.6 - 88.4%) reported that for most of the day they were within a 15 minute drive from home. We estimated that due to the mis-specification of the day of stroke onset, the risk of hospitalization for stroke would be understated by 15% and 20%, for NO2 and PM2.5, respectively.
Our data suggest that day of presentation and residential location data obtained from administrative records reasonably captures the time and location of stroke onset for most patients. Under these conditions, any associated errors are unlikely to be an important source of bias when estimating air pollution risks in this population.
Air pollution; stroke; survey; emergency service
Communication and coordination with primary care physicians (PCPs) is recommended to ensure safe care transitions for hospitalized older patients. Understanding patient experiences of problems after discharge can help clinical teams design more patient-centered care transitions.
To report older patients’ experiences with problems after hospital discharge and investigate whether PCPs were aware of their hospitalization
Prospective mixed methods study
Single academic medical center
Hospitalized patients and PCPs
Telephone interviews of older frail general medical patients conducted two weeks after discharge to elicit patient problems after discharge, such as obtaining medications, or follow-up appointments; and 2) perceptions of hospital physician communication with their PCP. For each patient interviewed, their PCP was faxed a survey two weeks after discharge to assess awareness of hospitalization.
Forty-two percent (27) of patients reported 42 different post-discharge problems. The most frequently reported problems were difficulty with follow-up appointments or tests (12). Other reported problems included readmission and return to the Emergency Department (10), problems with medications (8), not-prepared for discharge (8), and hospital complications or questions (4). Thirty percent of PCPs were unaware of patient hospitalization. Patients were twice as likely to report a problem if their PCP was unaware of the hospitalization (31% PCP aware, vs. 67% PCP not aware; p<0.05).
This study suggests that many frail older patients reported problems after discharge and were twice as likely to do so when the patient’s PCP was not aware of the hospitalization. Systematic interventions to improve communication with PCPs during patient hospitalization are needed.
communication; awareness; problems
The Chronic Care Model (CCM) is a multidimensional framework designed to improve care for patients with chronic health conditions. The model strives for productive interactions between informed, activated patients and proactive practice teams, resulting in better clinical outcomes and greater satisfaction. While measures for improving care may be clear, measures of residents’ competency to provide chronic care do not exist. This report describes the process used to develop educational measures and results from CCM settings that used them to monitor curricular innovations.
Twenty-six academic health care teams participating in the national and California Academic Chronic Care Collaboratives.
Using successive discussion groups and surveys, participants engaged in an iterative process to identify desirable and feasible educational measures for curricula that addressed educational objectives linked to the CCM. The measures were designed to facilitate residency programs’ abilities to address new accreditation requirements and tested with teams actively engaged in redesigning educational programs.
Field notes from each discussion and lists from work groups were synthesized using the CCM framework. Descriptive statistics were used to report survey results and measurement performance.
Work groups generated educational objectives and 17 associated measurements. Seventeen (65%) teams provided feasibility and desirability ratings for the 17 measures. Two process measures were selected for use by all teams. Teams reported variable success using the measures. Several teams reported use of additional measures, suggesting more extensive curricular change.
Using an iterative process in collaboration with program participants, we successfully defined a set of feasible and desirable education measures for academic health care teams using the CCM. These were used variably to measure the results of curricular changes, while simultaneously addressing requirements for residency accreditation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1358-1) contains supplementary material, which is available to authorized users.
Chronic Care Model; quality improvement; graduate medical education; ambulatory care; practice-based learning and improvement; systems-based practice
Two chronic care collaboratives (The National Collaborative and the California Collaborative) were convened to facilitate implementing the chronic care model (CCM) in academic medical centers and into post-graduate medical education.
We developed and implemented an electronic team survey (ETS) to elicit, in real-time, team member’s experiences in caring for people with chronic illness and the effect of the Collaborative on teams and teamwork.
The ETS is a qualitative survey based on Electronic Event Sampling Methodology. It is designed to collect meaningful information about daily experience and any event that might influence team members’ daily work and subsequent outcomes.
Forty-one residency programs from 37 teaching hospitals participated in the collaboratives and comprised faculty and resident physicians, nurses, and administrative staff.
Each team member participating in the collaboratives received an e-mail with directions to complete the ETS for four weeks during 2006 (the National Collaborative) and 2007 (the California Collaborative).
At the team level, the response rate to the ETS was 87% with team members submitting 1,145 narrative entries. Six key themes emerged from the analysis, which were consistent across all sites. Among teams that achieved better clinical outcomes on Collaborative clinical indicators, an additional key theme emerged: professional work satisfaction, or “Joy in Work”. In contrast, among teams that performed lower in collaborative measures, two key themes emerged that reflected the effect of providing care in difficult institutional environments—“lack of professional satisfaction” and awareness of “system failures”.
The ETS provided a unique perspective into team performance and the day-to-day challenges and opportunities in chronic illness care. Further research is needed to explore systematic approaches to integrating the results from this study into the design of improvement efforts for clinical teams.
chronic illness; team; joy in work; graduate medical education; ambulatory training; interprofessional training
Recent Breakthrough Series Collaboratives have focused on improving chronic illness care, but few have included academic practices, and none have specifically targeted residency education in parallel with improving clinical care. Tools are available for assessing progress with clinical improvements, but no similar instruments have been developed for monitoring educational improvements for chronic care education.
To design a survey to assist teaching practices with identifying curricular gaps in chronic care education and monitor efforts to address those gaps.
During a national academic chronic care collaborative, we used an iterative method to develop and pilot test a survey instrument modeled after the Assessing Chronic Illness Care (ACIC). We implemented this instrument, the ACIC-Education, in a second collaborative and assessed the relationship of survey results with reported educational measures.
A combined 57 self-selected teams from 37 teaching hospitals enrolled in one of two collaboratives.
We used descriptive statistics to report mean ACIC-E scores and educational measurement results, and Pearson’s test for correlation between the final ACIC-E score and reported educational measures.
A total of 29 teams from the national collaborative and 15 teams from the second collaborative in California completed the final ACIC-E. The instrument measured progress on all sub-scales of the Chronic Care Model. Fourteen California teams (70%) reported using two to six education measures (mean 4.3). The relationship between the final survey results and the number of educational measures reported was weak (R2 = 0.06, p = 0.376), but improved when a single outlier was removed (R2 = 0.37, p = 0.022).
The ACIC-E instrument proved feasible to complete. Participating teams, on average, recorded modest improvement in all areas measured by the instrument over the duration of the collaboratives. The relationship between the final ACIC-E score and the number of educational measures was weak. Further research on its utility and validity is required.
chronic care; ambulatory care; graduate medical education; assessment; quality improvement
There is a gap between the need for patient-centered, evidence-based primary care for the large burden of chronic illness in the US, and the training of resident physicians to provide that care.
To improve training for residents who provide chronic illness care in teaching practice settings.
US teaching hospitals were invited to participate in one of two 18-month Breakthrough Series Collaboratives—either a national Collaborative, or a subsequent California Collaborative—to implement the Chronic Care Model (CCM) and related curriculum changes in resident practices. Most practices focused on patients with diabetes mellitus. Educational redesign strategies with related performance measures were developed for curricular innovations anchored in the CCM. In addition, three clinical measures—HbA1c <7%, LDL <100 mg/dL, and blood pressure ≤130/80—and three process measures—retinal and foot examinations, and patient self-management goals—were tracked.
Fifty-seven teams from 37 self-selected teaching hospitals committed to implement the CCM in resident continuity practices; 41 teams focusing on diabetes improvement participated over the entire duration of one of the Collaboratives.
Teaching-practice teams—faculty, residents and staff—participated in Collaboratives by attending monthly calls and regular 2-day face-to-face meetings with the other teams. The national Collaborative faculty led calls and meetings. Each team used rapid cycle quality improvement (PDSA cycles) to implement the CCM and curricular changes. Teams reported education and clinical performance measures monthly.
Practices underwent extensive redesign to establish CCM elements. Education measures tracked substantial development of CCM-related learning. The clinical and process measures improved, however inconsistently, during the Collaboratives.
These initiatives suggest that systematic practice redesign for implementing the CCM along with linked educational approaches are achievable in resident continuity practices. Improvement of clinical outcomes in such practices is daunting but achievable.
residency training; chronic illness; teaching hospitals; Chronic Care Model