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1.  Race-Ethnic Differences in Factors Associated with Inhaled Steroid Adherence among Adults with Asthma 
Rationale: Adherence to inhaled corticosteroid (ICS) medication is known to be low overall, but tends to be lower among African-American patients when compared with white patients.
Objectives: To understand the factors that contribute to ICS adherence among African-American and white adults with asthma.
Methods: Eligible individuals had a prior diagnosis of asthma, one or more ICS prescriptions, and were members of a large health maintenance organization in southeast Michigan. Individuals were sent a survey that included questions about internal factors (e.g., patient beliefs, knowledge, and motivation) and external factors (e.g., socioeconomic status, barriers to care, social support, and stressors) potentially related to ICS adherence. Adherence was calculated using electronic prescription and fill data. Stepwise regression was used to identify factors associated with adherence before and after stratifying by race-ethnicity.
Measurements and Main Results: Surveys were returned by 1,006 (56.3%) of 1,787 eligible patients. Adjusting for internal factors, but not external factors, diminished the relationship between race-ethnicity and ICS adherence. Among African-American patients, readiness to take ICS medication was the only internal or external factor significantly associated with ICS adherence; it explained 5.6% of the variance in adherence. Among white patients, perceived ICS necessity, ICS knowledge, doctors being perceived as the source of asthma control, and readiness to take medication were the internal factors associated with ICS adherence; these accounted for 19.8% of the variance in adherence.
Conclusions: Factors associated with ICS adherence appear to differ between African-American and white patients, suggesting that group-specific approaches are needed to improve adherence.
PMCID: PMC2599867  PMID: 18849496
medication adherence; inhaled corticosteroids; asthma; race-ethnicity; patient compliance
2.  The role of endotoxin and its receptors in allergic disease 
To summarize the existing literature on the association of endotoxin with respiratory diseases and allergic sensitization and to review the potentially modifying effects of endotoxin receptor polymorphisms.
Data Sources
English-language articles were identified from the MEDLINE and PubMed databases using combinations of the following search terms: endotoxin, toll-like receptor, polymorphisms, atopy, asthma, and allergy. Other sources included experts in the field and the bibliographies of pertinent articles.
Study Selection
Relevant articles were selected based on the authors’ expert opinion.
Cross-sectional studies, particularly those of children raised in rural European communities, suggest that early endotoxin exposure may protect against the development of allergic sensitization and atopic asthma. However, endotoxin exposure may also contribute to other nonatopic respiratory disorders and may exacerbate disease in individuals with preexisting asthma. Paradoxically, among individuals exposed to high levels of endotoxin, carriers of a functional mutation in toll-like receptor 4, which reduces cellular responsiveness to endotoxin, may be at lower risk of developing allergic sensitization.
The effect of endotoxin exposure on allergic sensitization and asthma appears to be influenced by the timing of exposure, the presence or absence of preexisting disease, and polymorphisms in the genes that encode endotoxin receptors. Further studies are needed to define the window period for this effect, as well as the underlying immunologic mechanism.
PMCID: PMC1351105  PMID: 15801242
3.  Examining the relationship between depression and asthma exacerbations in a prospective follow-up study 
Psychosomatic medicine  2013;75(3):305-310.
While depression has been linked with asthma in numerous studies, its relationship with asthma exacerbations, including emergency room (ER) visits and oral steroid (OS) use has not been well documented. The main aim is to investigate whether comorbid depression increases exacerbations among patients with asthma.
The study included 568 participants with asthma, who were between 18-56 years old, were taking an inhaled corticosteroid, and participated in both baseline and follow-up surveys. Surveys and medical records from a large, integrated health system were collected as part of the Adherence Feedback for Improving Respiratory Medication Use trial ( NCT00459368). Number of ER visits and OS prescription fills for asthma were calculated for 12-month periods before and after the follow-up survey. Depression was measured using a standardized two-item instrument on both surveys. Negative binomial regression and modified proportional hazards models were used in the analyses.
Among patients with asthma, those who had depression (n=187; 32.9%) were at increased risk of having an asthma-related ER visit (adjusted relative risk (aRR): 1.96, 95% confidence interval (CI): 1.02 - 3.75), but not an OS fill (aRR: 0.98; 95%CI: 0.72-1.32). Participants with depression and asthma, who also received psychiatric treatment via antidepressant medication (n=126; 22.2%) or psychotherapy (n=39; 6.9%), were more likely to have an ER visit (medication hazard ratio (HR): 2.09, 95%CI: 1.35-3.25; psychotherapy HR: 2.07, 95%CI: 1.38-3.22).
This study suggests a temporal relationship between depression and asthma-related ER visits. Research and practice must further consider the importance of these comorbid conditions.
PMCID: PMC3706985  PMID: 23440228
asthma; depression; emergency care; oral steroid; mental health services
4.  Effect of Ezetimibe on Major Atherosclerotic Disease Events and All-Cause Mortality 
The American journal of cardiology  2012;111(4):532-539.
Despite ezetimibe’s ability to reduce serum cholesterol levels, there are concerns over its vascular effects and whether it prevents or ameliorates atherosclerotic disease (AD). Our objective was to estimate the effect of ezetimibe use on major AD events and all-cause mortality and to compare these associations to those observed for hydroxy-methylglutaryl-CoA reductase inhibitor (i.e., statin) use. We identified 367 new ezetimibe users between November 1, 2002 and December 31, 2009. These individuals were ≥18 years of age and had no prior statin use. One to four statin user matches were identified for each ezetimibe user resulting in a total of 1,238 closely matched statin users. Pharmacy data and drug dosage information were used to estimate a moving window of ezetimibe and statin exposure for each day of study follow-up. The primary outcome was a composite of major AD events (coronary heart disease, cerebrovascular disease, and peripheral vascular disease events) and all-cause death. Both ezetimibe use (odds ratio [OR] 0.33, 95% CI 0.13–0.86) and statin use (OR 0.61, 95% CI 0.36–1.04) were associated with reductions in the likelihood of the composite outcome. These protective associations were most significant for cerebrovascular disease events and all-cause death. Subgroup analyses by sex, race-ethnicity, prior history of AD, diabetes status, and estimated renal function showed consistent estimates across strata with no significant differences between ezetimibe and statin use. In conclusion, ezetimibe appeared to have a protective effect on major AD events and all-cause death which was not significantly different from that observed for statin use.
PMCID: PMC3563770  PMID: 23219178
ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; pharmacoepidemiology; atherosclerosis; cardiovascular disease; all-cause death
6.  Comparison of Beta Blocker Effectiveness in Heart Failure Patients with Preserved Ejection Fraction vs. those with Reduced Ejection Fraction 
Journal of cardiac failure  2013;19(2):73-79.
To compare the benefit of Beta Blockers (BB) in heart failure (HF) with preserved vs. reduced ejection fraction (EF).
Methods and Results
Retrospective study of insured patients who were hospitalized for HF between January 2000 and June 2008. Pharmacy claims were used to estimate BB exposure over six-month rolling windows. The association between BB exposure and all-cause hospitalization or death was tested using time-updated proportional hazards regression, with adjustment for baseline covariates and other HF medication exposure. The groups were compared by stratification (EF <50% vs. ≥50%) and using an EF-group*BB exposure interaction term. 1835 patients met inclusion criteria; 741 (40%) with a preserved EF. Median follow up was 2.1 years. In a fully-adjusted multivariable model, BB exposure was associated with a decreased risk of death or hospitalization in both groups (EF<50% hazard ratio [HR] 0.53, p<0.0001; EF≥50% HR 0.68, p=0.009). There was no significant difference in this protective association between groups (interaction p=0.32).
BB exposure was associated with a similar protective effect in terms of time to death or hospitalization in HF patients regardless of whether EF was preserved or reduced. An adequately powered randomized trial of BB in HF with preserved EF is warranted.
PMCID: PMC3678365  PMID: 23384631
beta adrenergic receptor blocker; hospitalization; diastolic dysfunction; heart failure with preserved ejection fraction
7.  Genetic ancestry and its association with asthma exacerbations among African American patients with asthma 
There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American individuals are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care, or whether there is a predisposing genetic component.
To assess the relationship between genetic ancestry and severe exacerbations among African American individuals with asthma.
Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These individuals were 12–56 years of age; received care from a single, large health system; and had a physician diagnosis of asthma. Genetic ancestry was estimated using a set of validated ancestry informative markers. Severe exacerbations (i.e., asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.
We assessed genetic ancestry in 392 African American individuals with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among males but not among females. The association among males persisted after adjusting for potential confounders (relative risk of 4.30 for every 20% increase in African ancestry; P-value 0.029).
African ancestry was a significantly and positively associated with severe exacerbations among African American males. These findings suggest that a portion of the risk of asthma exacerbations in this high risk group is attributable to a genetic risk factor which partitions with ancestry.
PMCID: PMC3511609  PMID: 23069492
asthma; continental population groups; African continental ancestry group; genetic association study; health status disparities; minority health
8.  Genetic variation in BAFF and asthma exacerbations among African American individuals 
Capsule Summary
A BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFF expression in vivo increases in natural rhinovirus infection. BAFF may play a role in airway antiviral immunity and impact asthma exacerbation rates.
PMCID: PMC3520130  PMID: 22728080
BAFF; B-cell activating factor; tumor necrosis factor ligand superfamily; asthma; asthma exacerbations; genetics
9.  Racial Disparities in Lipid Control in Patients With Diabetes 
To describe lipid management over time in a cohort of insured patients with diabetes and evaluate differences between African American and white patients.
Study Design
Automated claims data were used to identify a cohort of 11,411 patients with diabetes in 1997 to 1998. Patients were followed through 2007.
Rates of hypercholesterolemia testing, treatment, and goal attainment were measured annually. Treatment was determined by a claim for lipid-lowering agents, and goal attainment was defined as a low-density lipoprotein cholesterol (LDL-C) level <100 mg/dL.
During the study period, LDL-C testing increased from 48% to 70% among African American patients and from 61% to 77% among white patients. Treatment with lipid-lowering drugs increased from 23% to 56% among African American patients and 33% to 61% among white patients. The proportion at goal increased from 35% to 76% and from 24% to 59% among white and African American patients, respectively. African American patients were less likely to be tested for LDL-C (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.73–0.86), treated with lipid-lowering agents (OR 0.72; 95% CI 0.65–0.80), have their medication dosage altered (OR 0.65; 95% CI 0.59–0.73), or attain LDL-C goal (OR 0.59; 95% CI 0.56–0.63) compared with white patients.
Although rates of LDL-C testing, treatment, and goal attainment improved over time, racial disparities in dyslipidemia management continued to exist. Further studies to determine the causes of differences in management by race are warranted.
PMCID: PMC3766626  PMID: 22774998
10.  Comparison of Renal Predictors for In-Hospital and Post-Discharge Mortality after Hospitalized Heart Failure 
Abnormal baseline and acutely worsening renal function (WRF) during heart failure (HF) hospitalization are associated with worse outcomes. However, which renal criterion is most predictive of in-hospital and post-discharge mortality is uncertain.
We analyzed patients hospitalized for HF between January 1, 2000 and June 30, 2008. Preexisting end-stage renal disease was excluded. Blood urea nitrogen (BUN), creatinine (Cr), and MDRD-estimated glomerular filtration rate (eGFR) at admission and during hospitalization were tested for association with in-hospital and 1-year mortality. Logistic regression and conditional receiver operating curves were used to compare criterion in terms of association with mortality.
Among 7,394 patients, 204 died in-hospital, and 1,652 within 1 year. Admission BUN was the strongest correlate for both in-hospital and post-discharge mortality (area under curve [AUC]= 0.724 and 0.656; p<0.001 vs. Cr/eGFR), showing 4.6 and 3.0 fold mortality, respectively. Adjusting for baseline BUN, subsequent changes in Cr and BUN performed similarly for in-hospital death (model AUC 0.812; p<0.001 vs. eGFR) and post-discharge death (all similar, model AUC=0.661). Optimally predictive thresholds of WRF in hospital were dependant on the baseline renal function, and did not always correspond to common definitions.
Among hospitalized HF patients, baseline BUN is the renal index most strongly associated with in-hospital and one year mortality. WRF definitions that use BUN or Cr, have similar discriminative ability overall, but commonly used thresholds are suboptimal for predicting mortality; optimal thresholds varied with baseline renal function and time horizon.
PMCID: PMC3725607  PMID: 22343264
Renal function; BUN; Mortality; Heart Failure; Acutely Decompensated Heart Failure
11.  The relationship between combination inhaled corticosteroid and long-acting beta-agonist use and severe asthma exacerbations in a diverse population 
Safety concerns surround the use of long-acting beta agonists (LABA) for the treatment of asthma, even in combination with inhaled corticosteroids (ICS) and particularly in high-risk subgroups.
To estimate the effect ICS therapy and fixed-dose ICS/LABA combination therapy on severe asthma exacerbations in a racially diverse population.
Inhaled corticosteroid and ICS/LABA exposure was estimated from pharmacy data for patients with asthma age 12 to 56 years who were members of a large health maintenance organization. Inhaled corticosteroid and ICS/LABA use was estimated for each day of follow-up to create a moving window of exposure. Proportional hazard models were used to assess the relationship between ICS and ICS/LABA combination therapy and severe asthma exacerbations (i.e., use of oral corticosteroids, asthma-related emergency department visit, or asthma-related hospitalization).
Among the 1,828 patients who met the inclusion criteria, 37% were African American, 46% were treated with ICS therapy alone, and 54% were treated with an ICS/LABA combination. Models assessing the risk of severe asthma exacerbations among individuals using ICS treatment alone and ICS/LABA combination therapy suggested that the overall protective effect was as good or better for ICS/LABA combination therapy when compared with ICS treatment alone (hazard ratio [HR]=0.65 vs. HR=0.72, respectively). Analyses in several subgroups, including African American patients, showed a similar statistically significant protective association for combination therapy.
Treatment with ICS/LABA fixed combination therapy appeared to perform as well or better than ICS alone in reducing severe asthma exacerbations; this included multiple high-risk subgroups.
PMCID: PMC3340459  PMID: 22281166
Long-acting beta-agonist; inhaled corticosteroid; severe asthma exacerbation; safety; racially and ethnically diverse population; observational study
12.  Relationship of Loop Diuretic Dosing and Acute Changes in Renal Function during Hospitalization for Heart Failure 
Worsening renal function (WRF) during heart failure (HF) hospitalization is an accepted correlate of poor prognosis. Loop diuretics are increasingly being considered as a potential cause of worsened HF outcomes, perhaps via WRF. However, the magnitude of worsening in renal function attributable to loop diuretics has not been quantified.
This was a retrospective cohort study of patients who received care from a large health system and had a primary hospital discharge diagnosis of HF between Jan 1, 2000 and June 30, 2008. Patients with preexisting end-stage renal disease were excluded. Daily creatinine (Cr) measurements, furosemide dosing (only loop diuretic on hospital formulary), and radiocontrast dye studies were collected using administrative data. Day-to-day changes in Cr and MDRD estimated glomerular filtration (eGFR) were calculated. The first Cr or eGFR value during hospitalization or in the emergency department was considered baseline. Generalized estimating equations were used to test the association furosemide exposure over previous 2 days to the daily change in Cr and eGFR. Covariates included undergoing radiocontrast study, age, race, gender, and baseline Cr or eGFR.
Among 6071 patients who met inclusion criteria there were a total of 20,645 observations. This cohort was 51% female, 68% African American, and baseline Cr was 1.36 mg/dl. Furosemide exposure was associated with an average daily increase in Cr of 0.021 mg/dL and decrease in eGFR of 0.72 ml/min/1.73m2 (per 100 mg furosemide daily, both p<0.001). Over a typical length of stay of 5 days this would amount to a Cr increase of 0.11 mg/dL or decrease in eGFR of 3.6 ml/min/1.73m2. Furosemide exposure accounted for only 0.4% and 0.1% of the variation in Cr and eGFR changes, respectively. Undergoing radiocontrast study, African American race, and higher age were associated with day-to-day creatinine increases (all p<0.01). Reanaysis after classifying furosemide exposure into low (<40mg/day), medium (40–100mg/day), and high (>100mg/day) and censoring patients-days after radiocontrast exposure did not significantly affect the magnitude of the worsening renal function.
While loop diuretic exposure is statistically associated with WRF among hospitalized HF patients, the associated magnitude of renal function change is very small, and loop diuretics explain little of the variability in renal function during hospitalization. More important explanatory factors likely exist but remain unidentified.
PMCID: PMC3593064  PMID: 23482899
Heart failure; Cardiorenal syndrome; Acute renal failure; Morbidity; Furosemide
13.  Association of Beta Blocker Exposure with Outcomes in Heart Failure Patients Differs between African American and White Patients 
Circulation. Heart Failure  2012;5(2):202-208.
Beta blockers (BB) are a mainstay of heart failure (HF) treatment, yet there is inconclusive data regarding their efficacy in African American individuals.
Methods and Results
We performed a retrospective study of insured patients who received care from a large health system who were hospitalized for HF between January, 2000 and June, 2008, and had a documented ejection fraction <50%. BB exposure was estimated over six-month rolling windows using pharmacy claims data. Proportional hazards regression was used to test the association between BB exposure and all-cause hospitalization or death with adjustment for baseline covariates and other HF medication exposure. We performed analyses stratified by race, and overall with a BB exposure*Race interaction term. A total of 1,094 patients met inclusion criteria (476 white and 618 African American individuals). Median follow up was 2.1 years. In adjusted models BB exposure was associated with lower risk of death or hospitalization in both groups, but more so in white individuals (HR 0.40, 95%CI 0.27, 0.60, p<0.001) compared with African American individuals (HR 0.67, 95%CI 0.48, 0.94, p=0.024). A formal test for interaction indicated that the protection association for BB exposure differed by race (p=0.098, β=0.40). Reanalysis restricted to BBs approved for HF, or HF-specific hospitalizations did not substantively alter the findings.
BB appears to be 40–50% less effective in preventing death or hospitalization among African American patients with HF as compared with white individuals. Further study is needed to better understand BB effectiveness in African Americans with HF.
PMCID: PMC3310966  PMID: 22260944
heart failure; beta adrenergic receptor blocker; race; hospitalization; systolic dysfunction; adherence
14.  Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid non-adherence 
Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, individuals with asthma may have waxing and waning adherence to controller therapy.
To measure changes in inhaled corticosteroid (ICS) adherence over time, and to estimate the effect of this changing pattern of use on asthma exacerbations.
ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). For each individual we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations.
Adherence to ICS medications began to increase prior to the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations, but was only statistically significant among individuals whose adherence was >75% of the prescribed dose (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.41–0.90) when compared with individuals whose adherence was ≤25%. This pattern was largely confined to individuals whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication non-adherence.
Inhaled corticosteroid adherence varies in the time period leading up to and following an asthma exacerbation, and non-adherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events. [ number NCT01142947]
PMCID: PMC3229671  PMID: 22019090
medication adherence; inhaled corticosteroids; asthma; patient compliance; asthma exacerbations
15.  Ethnic Variability in Persistent Asthma After In Utero Tobacco Exposure 
Pediatrics  2011;128(3):e623-e630.
The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent.
To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children.
There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression.
Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year.
Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.
PMCID: PMC3164096  PMID: 21859918
asthma; tobacco; Latino; African American; pregnancy
16.  Genetic Ancestry-Smoking Interactions and Lung Function in African Americans: A Cohort Study 
PLoS ONE  2012;7(6):e39541.
Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans.
Methodology/Principal Findings
We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV1) per pack-year of smoking (−5.7 ml FEV1/ smoking pack-year) compared with smokers with lower African ancestry (−4.6 ml in FEV1/ smoking pack-year) (interaction P value  = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV1 decline in Health ABC and independently replicated in CARDIA.
African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.
PMCID: PMC3380861  PMID: 22737244
17.  Relation of Worsened Renal Function during Hospitalization for Heart Failure to Long-Term Outcomes and Rehospitalization 
Worsened renal function (WRF) during heart failure (HF) hospitalization is associated with in-hospital mortality, but there are limited data regarding its relationship to long-term outcomes after discharge. The influence of WRF resolution is also unknown. This retrospective study analyzed patients who received care from a large health system and had a primary hospital discharge diagnosis of HF between 1/2000 and 6/2008. Renal function was estimated from creatinine levels during hospitalization. The first available value was considered baseline. WRF was defined a creatinine increase of ≥0.3mg/dl on any subsequent hospital day compared to baseline. Persistent WRF was defined as having WRF at discharge. Proportional hazards regression, adjusting for baseline renal function and potential confounding factors, was used to assess time to re-hospitalization or death. Among 2465 patients who survived to discharge, 887 (36%) developed WRF. Median follow up was 2.1 years. In adjusted models, WRF was associated with higher rates of post-discharge death or re-hospitalization (HR 1.12, 95%CI 1.02 – 1.22). Among those with WRF, 528 (60%) had persistent WRF while 359 (40%) recovered. Persistent WRF was significantly associated with higher post-discharge event rates (HR 1.14, 95%CI 1.02 – 1.27), whereas transient WRF showed only a non-significant trend towards risk (HR 1.09 95%CI 0.96-1.24). In conclusion, among patients surviving hospitalization for HF, WRF was associated with increased long-term mortality and re-hospitalization, particularly if renal function did not recover by the time of discharge.
PMCID: PMC3016846  PMID: 21146690
heart failure; cardiorenal syndrome; mortality; morbidity
18.  A cluster-randomized trial to provide clinicians inhaled corticosteroid adherence information for their patients with asthma 
Inhaled corticosteroid (ICS) non-adherence is common among patients with asthma; however, interventions to improve adherence have often been complex and not easily applied to large patient populations.
To assess the effect of supplying patient adherence information to primary care providers.
Patients and providers were members of a health system serving southeast Michigan. Providers (88 intervention; 105 control) and patients (1,335 intervention; 1,363 control) were randomized together by practice. Patients were age 5–56 years; had a diagnosis of asthma; and had existing prescriptions for ICS medication. Adherence was estimated using prescription and fill data. Unlike clinicians in the control arm, intervention arm providers could view updated ICS adherence information on their patients via electronic prescription software, and further details on patient ICS use could be viewed by selecting that option. The primary outcome was ICS adherence in last 3-months of the study period.
At study end for the intention-to-treat analysis, ICS adherence was not different among patients in the intervention arm when compared with those in the control arm (21.3% vs. 23.3%, respectively; P=0.553). However, adherence was significantly higher among patients whose clinician elected to view their detailed adherence information (35.7%) when compared with both control arm patients (P=0.026) and intervention arm patients whose provider did not view adherence data (P=0.002).
Overall, providing adherence information to clinicians did not improve ICS use among patients with asthma. However, patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use.
PMCID: PMC2917519  PMID: 20569973
Medication adherence; inhaled corticosteroids; asthma; randomized controlled trial
19.  Genetic Ancestry in Lung-Function Predictions 
The New England journal of medicine  2010;363(4):321-330.
Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.
We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.
African ancestry was inversely related to forced expiratory volume in 1 second (FEV1) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV1) in 4 to 5% of participants.
Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
PMCID: PMC2922981  PMID: 20647190
20.  Relationship between thiazolidinedione use and cardiovascular outcomes and all-cause mortality among patients with diabetes: A time-updated propensity analysis 
To investigate the association of the thiazolidinediones (TZDs), rosiglitazone and pioglitazone, together and individually on the risk of cardiovascular outcomes and all-cause mortality, using time-updated propensity score adjusted analysis
We conducted a retrospective cohort study in a large vertically integrated health system in southeast Michigan. Cohort inclusion criteria included adult patients with diabetes treated with oral medications and followed longitudinally within the health system between January 1, 2000 and December 1, 2006. The primary outcome was fatal and non-fatal acute myocardial infarction. Secondary outcomes included hospitalizations for congestive heart failure, fatal and non-fatal cerebrovascular accidents and transient ischemic attacks, combined coronary heart disease events, and all-cause mortality.
19,171 patients were included in this study. Use of TZDs (adjusted hazard ratio [aHR] with propensity adjustment [PA], 0.92; 95% confidence interval [CI] 0.73–1.17), rosiglitazone (aHR with PA, 1.06; 95% CI 0.66–1.70), and pioglitazone (aHR with PA, 0.91; 95% CI 0.69–1.21) was not associated with a higher risk of acute myocardial infarction. However, pioglitazone use was associated with a reduction in all-cause mortality (aHR with PA, 0.60; 95% CI 0.42–0.96). Compared with rosiglitazone, pioglitazone use was associated with a lower risk of all outcomes assessed, particularly congestive heart failure (P = 0.013) and combined coronary heart disease events (P = 0.048).
Our findings suggest that pioglitazone may have a more favorable risk profile when compared to rosiglitazone, arguing against a singular effect for TZDs on cardiovascular outcomes.
PMCID: PMC2919167  PMID: 19235778
Thiazolidinediones; Coronary Heart Disease; Congestive Heart Failure; Cerebrovascular Accident; Mortality
21.  Reducing the Health Risks of Diabetes: How Self-determination Theory May Help Improve Medication Adherence and Quality of Life 
The Diabetes educator  2009;35(3):484-492.
The purpose of this study was to apply the self-determination theory (SDT) model of health behavior to predict medication adherence, quality of life, and physiological outcomes among patients with diabetes.
Patients with diabetes (N = 2,973) receiving care from an integrated health-care delivery system in 2003 and 2004 were identified from automated databases and invited to participate in this study. In 2005, patients responded to a mixed telephone-and-mail survey assessing perceived autonomy-support from health-care providers, autonomous self-regulation for medication use, perceived competence for diabetes self-management, medication adherence, and quality of life. In 2006, we used pharmacy-claims data to indicate medication adherence and we assessed patients’ non-HDL cholesterol, HbA1c, and glucose levels.
The SDT model of health behavior provided adequate fit to the data. As hypothesized, perceived autonomy-support from health-care providers related positively to autonomous self-regulation for medication use, which in turn related positively to perceived competence for diabetes self-management. Perceived competence then related positively to quality of life and medication adherence, and the latter construct related negatively to non-HDL cholesterol, HbA1c, and glucose levels.
Health-care providers’ support for patients’ autonomy and competence around medication use and diabetes self-management related positively to medication adherence, quality of life, and physiological outcomes among patients with diabetes.
PMCID: PMC2831466  PMID: 19325022
22.  Comparing methods for identifying patients with heart failure using electronic data sources 
Accurately indentifying heart failure (HF) patients from administrative claims data is useful for both research and quality of care efforts. Yet, there are few comparisons of the various claims data criteria (also known as claims signatures) for identifying HF patients. We compared various HF claim signatures to assess their relative accuracy.
In this retrospective study, we identified 4174 patients who received care from a large health system in southeast Michigan and who had ≥1 HF encounter between January 1, 2004 and December 31, 2005. Four hundred patients were chosen at random and a detailed chart review was performed to assess which met the Framingham HF criteria. The sample was divided into 300 subjects for derivation and 100 subjects for validation. Sensitivity, specificity,, and area under the curve (AUC) were determined for the various claim signatures. The criteria with the highest AUC were retested in the validation set.
Of the 400 patients sampled, 65% met Framingham HF criteria, and 56% had at least one B-type Natriuretic Peptide (BNP) measurement. There was substantial variation between claims signatures in terms of sensitivity (range 15%-77%) and specificity (range 69%-100%). The best performing criteria in the derivation set was if patients met any one of the following: ≥2 HF encounters, any hospital discharge diagnosis of HF, or a BNP ≥200 pg/ml. These criteria showed a sensitivity of 76%, specificity of 75%, and AUC of 0.754 for meeting the Framingham HF criteria. This claims signature performed similarly in the validation set.
Claim signatures for HF vary greatly in their relative sensitivity and specificity. These findings may facilitate efforts to identify HF patients for research and quality improvement efforts.
PMCID: PMC2804587  PMID: 20021648
23.  An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity 
Human Molecular Genetics  2008;17(17):2681-2690.
A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the β1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure – forced expiratory volume (FEV1) % of predicted value. The 818T allele is associated with a clinically significant decline (−13%) in FEV1 in both cohorts of asthmatics among males but not females (Pcombined = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the β1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.
PMCID: PMC2733805  PMID: 18535015
24.  Gene-environment interactions between CD14 C-260T and endotoxin exposure on Foxp3+ and Foxp3− CD4+ lymphocyte numbers and total serum IgE levels in early childhood 
Innate immune system stimuli, such as endotoxin, seem to affect allergy risk. Previously, we described gene-environment interactions between the endotoxin receptor polymorphism C-260T of the CD14 gene and endotoxin exposure on total serum IgE level; however, the mechanism of this interaction is not known.
To examine whether this gene-environment interaction affects early CD4+Foxp3− or CD4+Foxp3+ lymphocyte numbers.
Participating children were part of a birth cohort in the Detroit metropolitan area. Participants were genotyped for the CD14 C-260T polymorphism. Endotoxin exposure was estimated from dust measured in the home when children were 6 months old. Intracellular Foxp3 protein expression, a regulatory T-cell marker, was used to characterize CD4+ lymphocytes in blood samples collected at the age of 12 months; total serum IgE level was also measured at this time. Because race/ethnicity may confound or modify genetic associations, all analyses were stratified by race/ethnicity.
We observed a significant gene-environment interaction between CD14 C-260T genotype and endotoxin exposure on CD4+ lymphocyte numbers, particularly CD4+Foxp3− lymphocytes. Stratified analyses suggest effect modification by race/ethnicity on CD4+Foxp3+ lymphocyte numbers, with a significant interaction in African American children but not in white children. The interaction between CD14 C-260T genotype and endotoxin exposure on total IgE levels was opposite that observed for CD4+ lymphocyte numbers, suggesting reciprocal relationships.
A gene-environment interaction between endotoxin and CD14 C-260T genotype on IgE levels may be the result of an upstream, opposing effect on CD4+Foxp3+ and CD4+Foxp3− lymphocyte numbers. Race/ethnicity may affect which of these cell populations is affected by this gene-environment interaction.
PMCID: PMC2646830  PMID: 18320914
25.  Relationship between recent short-acting β-agonist use and subsequent asthma exacerbations 
US national guidelines recommend assessing short-acting β-agonist (SABA) medication use as a marker of asthma severity and control. However, the relationship between recent SABA use and asthma exacerbations is not currently known.
To evaluate the proximal relationship between the type and frequency of SABA use and asthma-related outcomes.
We evaluated SABA use among patients with asthma ages 5 to 56 years who were members of a large health maintenance organization in southeast Michigan. Frequency of use was estimated from pharmacy data assessing the timing and amount of SABA fills. Cox proportional hazards models were used to examine the prospective relationship between average daily SABA use for 3 months and outcomes associated with poor asthma control (ie, oral corticosteroids use, asthma-related emergency department visits, and asthma-related hospitalizations). We separately accounted for SABA metered-dose inhaler (MDI) and SABA nebulizer use.
Of the 2,056 patients who met study criteria, 1,569 (76.3%) had used a SABA medication in their baseline year. After adjusting for potential confounders, SABA nebulizer use was associated with asthma-related emergency department visits (adjusted hazard ratio [aHR], 6.32; 95% confidence interval [CI], 2.38 to 16.80) and asthma-related hospitalizations (aHR, 21.62; 95% CI, 3.17 to 147.57). In contrast, frequency of SABA MDI use was not associated with these outcomes.
Frequency of SABA use during a 3-month period was associated with poor asthma outcomes. The relationship with poor asthma outcomes was strongest for SABA nebulizer use, suggesting that the type of SABA used is also of prognostic importance.
PMCID: PMC2646829  PMID: 19055201

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