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1.  Life-Sustaining-Treatment Preferences: Matches and Mismatches Between Patients’ Preferences and Clinicians’ Perceptions 
Better clinician understanding of patients’ end-of-life-treatment preferences has the potential for reducing unwanted treatment, decreasing health care costs, and improving end-of-life care.
To investigate patient preferences for life-sustaining therapies, clinicians’ accuracy in understanding those preferences, and predictors of patient preference and clinician error.
Observational study of 196 male veterans with chronic obstructive pulmonary disease (COPD) who participated in a randomized trial. Measures included patients’ preferences for mechanical ventilation (MV) and cardiopulmonary resuscitation (CPR) if needed in their current state of health, and outpatient clinicians’ beliefs about those preferences.
Analyses were based on 54% of participants in the trial who had complete patient/clinician data on treatment preferences. Patients were more receptive to CPR than MV (76% vs. 61%; P<0.001). Preferences for both treatments were significantly associated with the importance patients assigned to avoiding life-sustaining therapies during the final week of life (MV: b=−0.11, P<0.001; CPR: b=−0.09, P=0.001). When responses were dichotomized (would/wouldn’t want treatment), physicians’ perceptions matched patient preferences in 75% of CPR cases and 61% of MV cases. Physician errors increased as patients preferred less aggressive treatment (MV: b=−0.28, P<0.001; CPR: b=−0.32, P<0.001).
Clinicians erred more often about patients’ wishes when patients did not want treatment than when they wanted it. Treatment decisions based on clinicians’ perceptions could result in costly and unwanted treatments. End-of-life care could benefit from increased clinician-patient discussion about end-of-life care, particularly if discussions included patient education about risks of treatment and allowed clinicians to form and maintain accurate impressions of patients’ preferences.
PMCID: PMC3534846  PMID: 23017611
treatment preferences; patient-clinician communication; chronic obstructive pulmonary disease; palliative care
2.  Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma 
Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma.
In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n=25,975, follow-up 3.0±1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV, and heart failure) and 4 conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates.
HIV followed by alcoholism and mental disorders among 18–45 years old, and heart failure, diabetes, IHD, and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder, and IHD among those ≥65 years old. GERD was associated with decreased risk for asthma exacerbation in all ages.
Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.
PMCID: PMC4067514  PMID: 24432868
observational study; Veterans; outcome research; comorbidities; mental disorders
3.  Measuring health-related quality of life in chronic obstructive pulmonary disease: properties of the EQ-5D-5L and PROMIS-43 short form 
The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases. The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function.
We conducted a multi-center, cross-sectional study (“COPD Outcomes-based Network for Clinical Effectiveness & Research Translation” [CONCERT]). We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires. Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered. Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed.
Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male). More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L. Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) correlated. A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles.
Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients.
PMCID: PMC4072614  PMID: 24934150
COPD; EQ-5D-5L; PROMIS; Psychometric properties
4.  Predictors of Adherence to Inhaled Medications 
PMCID: PMC3663956  PMID: 23529709
6.  Wide Clinic-Level Variation in Adherence to Oral Diabetes Medications in the VA 
While there has been extensive research into patient-specific predictors of medication adherence and patient-specific interventions to improve adherence, there has been little examination of variation in clinic-level medication adherence.
We examined the clinic-level variation of oral hypoglycemic agent (OHA) medication adherence among patients with diabetes treated in the Department of Veterans Affairs (VA) primary care clinics. We hypothesized that there would be systematic variation in clinic-level adherence measures, and that adherence within organizationally-affiliated clinics, such as those sharing local management and support, would be more highly correlated than adherence between unaffiliated clinics.
Retrospective cohort study.
VA hospital and VA community-based primary care clinics in the contiguous 48 states.
444,418 patients with diabetes treated with OHAs and seen in 158 hospital-based clinics and 401 affiliated community primary care clinics during fiscal years 2006 and 2007.
Refill-based medication adherence to OHA.
Adjusting for patient characteristics, the proportion of patients adherent to OHAs ranged from 57 % to 81 % across clinics. Adherence between organizationally affiliated clinics was high (Pearson Correlation = 0.82), and adherence between unaffiliated clinics was low (Pearson Correlation = 0.04).
The proportion of patients adherent to OHAs varied widely across VA primary care clinics. Clinic-level adherence was highly correlated to other clinics in the same organizational unit. Further research should identify which factors common to affiliated clinics influence medication adherence.
PMCID: PMC3631064  PMID: 23371383
pharmacoepidemiology; health services research; diabetes; veterans; primary care
7.  Missing Potential Opportunities to Reduce Repeat COPD Exacerbations 
Long-acting beta-agonists (LABA) and/or inhaled corticosteroids (ICS) have been shown to reduce COPD exacerbation risk. Using data from a large integrated health-care system, we sought to examine whether these medication classes were initiated after an exacerbation of COPD.
We identified patients who experienced an inpatient or outpatient COPD exacerbation within the Veterans Affairs Integrated Service Network (VISN)-20. We assessed the addition of a new inhaled therapy (an ICS, LABA or both) within 180 days after the exacerbation. We assessed independent predictors of adding treatment using logistic regression.
We identified 45,780 patients with COPD, of whom 2,760 patients experienced an exacerbation of COPD. Of these individuals, 2,570 (93.1 %) were on either none or only one long-acting medication studied (LABA or ICS). In the subsequent 180-day period after their exacerbation, only 875 (34.1 %) patients had at least one of these additional therapies dispensed from a VA pharmacy. Among patients who were treated in the outpatient setting, older age [OR 0.98/year, 95 % CI (0.97–0.99)], current tobacco use [OR 0.74, 95 % CI (0.60–0.90)], greater use of ipratropium bromide [OR 0.97/canister, 95 % CI (0.96–0.98)], prior COPD exacerbation [OR 0.55, 95 % CI (0.46–0.67)], depression [OR 0.77, 95 % CI (0.61–0.98)], CHF [OR 0.74, 95 % CI (0.57–0.97)], and diabetes (OR 0.77 (0.60–0.99)] were associated with lower odds of additional therapy. Patients who were treated in the hospital had similar associated predictors.
Among patients treated for an exacerbation of COPD, we found relatively few were subsequently prescribed inhaled therapies known to reduce exacerbations.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2276-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3631056  PMID: 23225255
COPD; exacerbation; inhaled medication use
8.  Obesity Is Associated With a Lower Resting Oxygen Saturation in the Ambulatory Elderly: Results From the Cardiovascular Health Study 
Respiratory care  2013;58(5):10.4187/respcare.02008.
The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population.
The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated.
Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = −0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m2 and ≥ 35 kg/m2) was 1.33% (95% CI 0.89–1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2–1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47–1.27, for African Americans).
We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2.
PMCID: PMC3885157  PMID: 23107018
pulse oximetry; oxygen; obesity; body mass index; waist circumference; hypoxemia; pulmonary function test
9.  Use of Spirometry in the Diagnosis of COPD: A Qualitative Study in Primary Care 
COPD  2013;10(4):444-449.
Guidelines that recommend spirometry to confirm airflow obstruction among patients with suspected COPD are not routinely followed. We conducted a qualitative study to identify attitudes and barriers of primary care physicians to performing spirometry for patients with possible COPD. We conducted four focus groups, each with three primary care physicians (PCPs) who practice in an urban, academic medical center. In general, PCPs believed that spirometry was not necessary to confirm the diagnosis of COPD. Compared to other co-morbid conditions, in a patient with a diagnosis of COPD without self-reported symptoms, COPD was not a priority during a clinic visit. This was in part due to the belief that there was lack of evidence that medication used in COPD lead to improved outcomes and that there was no point of care measure for COPD compared to other co-morbid conditions such as diabetes mellitus or hypertension. Health system barriers specific to spirometry use was not identified. In conclusion, in our sample of PCPs, there was skepticism that spirometry is warranted to diagnose and manage COPD. Availability of spirometry was not a perceived barrier. Our results explain, in part, why previous interventions to improve access to spirometry and diagnosis of COPD in primary care settings have been difficult to conduct and/or have had marginal success. Our findings strongly suggest that a first step toward increasing the use of spirometry among primary care physicians is to have them believe in its utility in the diagnosis of COPD.
PMCID: PMC3938329  PMID: 23537230
chronic disease; diagnosis; pulmonary diseases; qualitative research
10.  Stakeholder Priorities for Comparative Effectiveness Research in Chronic Obstructive Pulmonary Disease 
Comparative effectiveness research (CER) is intended to address the expressed needs of patients, clinicians, and other stakeholders. Representatives of 54 stakeholder groups with an interest in chronic obstructive pulmonary disease (COPD) participated in workshops convened by the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) over a 2-year period. Year 1 focused on chronic care and care coordination. Year 2 focused on acute care and transitions in care between healthcare settings. Discussions and provisional voting were conducted via teleconferences and e-mail exchanges before the workshop. Final prioritization votes occurred after in-person discussions at the workshop. We used a modified Delphi approach to facilitate discussions and consensus building. To more easily quantify preferences and to evaluate the internal consistency of rankings, the Analytic Hierarchy Process was incorporated in Year 2. Results of preworkshop and final workshop voting often differed, suggesting that prioritization efforts relying solely on requests for topics from stakeholder groups without in-person discussion may provide different research priorities. Research priorities varied across stakeholder groups, but generally focused on studies to evaluate different approaches to healthcare delivery (e.g., spirometry for diagnosis and treatment, integrated healthcare strategies during transitions in care) rather than head-to-head comparisons of medications. This research agenda may help to inform groups intending to respond to CER funding opportunities in COPD. The methodologies used, detailed in the online supplement, may also help to inform prioritization efforts for CER in other health conditions.
PMCID: PMC3603554  PMID: 23155144
health services research; research priorities; care coordination; stakeholders
11.  Predictors of Adherence to Inhaled Medications Among Veterans with COPD 
Journal of General Internal Medicine  2012;27(11):1506-1512.
Factors contributing to medication nonadherence among patients with chronic obstructive pulmonary disease (COPD) are poorly understood.
To identify patient characteristics that are predictive of adherence to inhaled medications for COPD and, for patients on multiple inhalers, to assess whether adherence to one medication class was associated with adherence to other medication classes.
Cohort study using data from Veteran Affairs (VA) electronic databases.
This study included 2,730 patients who underwent pulmonary function testing between 2003 and 2007 at VA facilities in the Northwestern United States, and who met criteria for COPD.
We used pharmacy records to estimate adherence to inhaled corticosteroids (ICS), ipratropium bromide (IP), and long-acting beta-agonists (LABA) over two consecutive six month periods. We defined patients as adherent if they had refilled medications to have 80 % of drug available over the time period. We also collected information on their demographics, behavioral habits, COPD severity, and comorbidities.
Adherence to medications was poor, with 19.8 % adherent to ICS, 30.6 % adherent to LABA, and 25.6 % adherent to IP. Predictors of adherence to inhaled therapies were highly variable and dependent on the medication being examined. In adjusted analysis, being adherent to a medication at baseline was the strongest predictor of future adherence to that same medication [(Odds ratio, 95 % confidence interval) ICS: 4.79 (3.22–7.12); LABA: 6.60 (3.92–11.11); IP: 14.13 (10.00–19.97)], but did not reliably predict adherence to other classes of medication.
Among patients with COPD, past adherence to one class of inhaled medication strongly predicted future adherence to the same class of medication, but only weakly predicted adherence to other classes of medication.
PMCID: PMC3475808  PMID: 22782274
medication adherence; pulmonary diseases; health behavior; veterans
12.  Does the presence of a pharmacist in primary care clinics improve diabetes medication adherence? 
Although oral hypoglycemic agents (OHAs) are an essential element of therapy for the management of type 2 diabetes, OHA adherence is often suboptimal. Pharmacists are increasingly being integrated into primary care as part of the move towards a patient-centered medical home and may have a positive influence on medication use. We examined whether the presence of pharmacists in primary care clinics was associated with higher OHA adherence.
This retrospective cohort study analyzed 280,603 diabetes patients in 196 primary care clinics within the Veterans Affairs healthcare system. Pharmacists presence, number of pharmacist full-time equivalents (FTEs), and the degree to which pharmacy services are perceived as a bottleneck in each clinic were obtained from the 2007 VA Clinical Practice Organizational Survey—Primary Care Director Module. Patient-level adherence to OHAs using medication possession ratios (MPRs) were constructed using refill data from administrative pharmacy databases after adjusting for patient characteristics. Clinic-level OHA adherence was measured as the proportion of patients with MPR >= 80%. We analyzed associations between pharmacy measures and clinic-level adherence using linear regression.
We found no significant association between pharmacist presence and clinic-level OHA adherence. However, adherence was lower in clinics where pharmacy services were perceived as a bottleneck.
Pharmacist presence, regardless of the amount of FTE, was not associated with OHA medication adherence in primary care clinics. The exact role of pharmacists in clinics needs closer examination in order to determine how to most effectively use these resources to improve patient-centered outcomes including medication adherence.
PMCID: PMC3537712  PMID: 23148570
Pharmacist; Medication adherence; Diabetes mellitus; Oral hypoglycemic agent; Patient-centered medical home
13.  Determinants of Spirometry Use and Accuracy of COPD Diagnosis in Primary Care 
Journal of General Internal Medicine  2011;26(11):1272-1277.
It is unclear if primary care physicians are following guidelines or using other patient characteristics and factors to determine when to perform spirometry in patients at risk for COPD. It is also unclear to what degree a diagnosis of COPD is accurately reflected by spirometry results.
To examine characteristics associated with use of spirometry in primary care for patients with increased risk for COPD and to determine the accuracy of COPD diagnosis in patients with spirometry.
Retrospective cohort study.
A cohort that met the following criteria was identified: ≥35 years of age; ≥ 2 primary care visits in internal medicine clinic in 2007; at least one respiratory or smoking cessation medication, or diagnosis of COPD or shortness of breath or dyspnea in 2007.
Main Measures
Medical records of all primary care physician visits prior to the time of inclusion in 2007 were reviewed. Data on patient demographics, co-morbidities, respiratory medication use, presence of symptoms, history of tobacco use, and pulmonary function tests were extracted.
Key Results
A total 1052 patients were identified. Dyspnea on exertion (Adjusted odds ratio (AOR) 1.52 [95% CI 1.06–2.18]) and chronic cough (AOR 1.71 [1.07–2.72]) were the only chronic symptoms associated with use of spirometry. Current (AOR 1.54 [0.99–2.40]) or past smoking (AOR 1.09 [0.72–1.65]) status were not associated with use of spirometry. Of the 159 patients with a diagnosis of COPD, 93 (58.5%) met GOLD criteria and 81(50.9%) met lower limit of normal (LLN) criteria for COPD.
Clinicians use spirometry more often among patients with symptoms suggestive of COPD but not more often among patients with current or past tobacco use. For patients who had a spirometry and a diagnosis of COPD, primary care physicians were accurate in their diagnosis only half of the time.
PMCID: PMC3208468  PMID: 21713542
chronic disease; diagnosis; health care delivery; chronic obstructive pulmonary disease; spirometry; quality of care
14.  Comparative effectiveness research in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease affects millions worldwide. It is America’s third leading cause of death, and results in significant morbidity and cost. Although many therapies exist and are being developed to alleviate symptoms and decrease morbidity and mortality in chronic obstructive pulmonary disease, most have only been studied in placebo-controlled efficacy studies in highly selected populations. Comparative effectiveness and translational research in chronic obstructive pulmonary disease will require the development of infrastructures to support collaboration between researchers and the stakeholders who generate, disseminate and use new knowledge. Methodologies need to evolve to both prioritize research questions and to conduct collaborative comparative effectiveness research studies. Given the impracticality of testing every clinical intervention in comparative pragmatic trials for comparative effectiveness research in chronic obstructive pulmonary disease, we advocate expanding methodology that includes the use of observational databases with serially performed effectiveness analyses and quasi-experimental designs that include following healthcare changes longitudinally over time to assess benefit, harm, subgroups and cost.
PMCID: PMC3479302  PMID: 23105965
chronic obstructive pulmonary disease; comparative effectiveness research; data warehouse; emphysema; health services research; outcome research; quasi-experimental design; registry; translational research
15.  Comparative Effectiveness Research in Lung Diseases and Sleep Disorders 
The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) held a workshop to develop recommendations on topics, methodologies, and resources for comparative effectiveness research (CER) that will guide clinical decision making about available treatment options for lung diseases and sleep disorders. A multidisciplinary group of experts with experience in efficacy, effectiveness, implementation, and economic research identified (a) what types of studies the domain of CER in lung diseases and sleep disorders should include, (b) the criteria and process for setting priorities, and (c) current resources for and barriers to CER in lung diseases. Key recommendations were to (1) increase efforts to engage stakeholders in developing CER questions and study designs; (2) invest in further development of databases and other infrastructure, including efficient methods for data sharing; (3) make full use of a broad range of study designs; (4) increase the appropriate use of observational designs and the support of methodologic research; (5) ensure that committees that review CER grant applications include persons with appropriate perspective and expertise; and (6) further develop the workforce for CER by supporting training opportunities that focus on the methodologic and practical skills needed.
PMCID: PMC3265273  PMID: 21965016
randomized controlled trials; observational studies; implementation; study designs; methodology
16.  Obesity and COPD: Associated Symptoms, Health-related Quality of Life, and Medication Use 
COPD  2011;8(4):275-284.
There is little data about the combined effects of COPD and obesity. We compared dyspnea, health-related quality of life (HRQoL), exacerbations, and inhaled medication use among patients who are overweight and obese to those of normal weight with COPD.
We performed secondary data analysis on 364 Veterans with COPD. We categorized subjects by body mass index (BMI). We assessed dyspnea using the Medical Research Council (MRC) dyspnea scale and HRQoL using the St. George's Respiratory Questionnaire. We identified treatment for an exacerbation and inhaled medication use in the past year. We used multiple logistic and linear regression models as appropriate, with adjustment for age, COPD severity, smoking status, and comorbidities.
The majority of our population was male (n=355, 98%) and either overweight (n=115, 32%) or obese (n=138, 38%). Obese and overweight subjects had better lung function (obese: mean FEV1 55.4% ±19.9% predicted, overweight: mean FEV1 50.0% ±20.4% predicted) than normal weight subjects (mean FEV1 44.2% ±19.4% predicted), yet obese subjects reported increased dyspnea [adjusted OR of MRC score ≥2= 4.91 (95% CI 1.80, 13.39], poorer HRQoL, and were prescribed more inhaled medications than normal weight subjects. There was no difference in any outcome between overweight and normal weight patients.
Despite having less severe lung disease, obese patients reported increased dyspnea and poorer HRQoL than normal weight patients. The greater number of inhaled medications prescribed for obese patients may represent overuse. Obese patients with COPD likely need alternative strategies for symptom control in addition to those currently recommended.
PMCID: PMC3169653  PMID: 21809909
Obesity; COPD; health-related quality of life; symptoms; inhaled medications; exacerbations
17.  Disparities in lung cancer staging with positron emission tomography in the Cancer Care Outcomes Research and Surveillance (CanCORS) study 
Disparities in treatment exist for non-white and Hispanic patients with non-small-cell lung cancer, but little is known about disparities in the use of staging tests or their underlying causes.
Prospective, observational cohort study of 3638 patients with newly diagnosed non-small-cell lung cancer from 4 large, geographically-defined regions, 5 integrated health care systems and 13 VA health care facilities.
Median age was 69 years, 62% were men, 26% were Hispanic or non-white, 68% graduated high school, 50% had private insurance, and 41% received care in the VA or another integrated health care system. After adjustment, PET use was 13% lower among non-whites and Hispanics than non-Hispanic whites (RR 0.87, 95% CI 0.77 to 0.97), 13% lower among those with Medicare than those with private insurance (RR 0.87, 95% CI 0.76 to 0.99), and 24% lower among those with an elementary school education than those with a graduate degree (RR 0.76, 95% CI 0.57 to 0.98). Disparate use of PET was not observed among patients who received care in an integrated health care setting, but the association between race/ethnicity and PET use was similar in magnitude across all other subgroups. Further analysis showed that income, education, insurance and health care setting do not explain the association between race/ethnicity and PET use.
Hispanics and non-whites with non-small-cell lung cancer are less likely to receive PET imaging. This finding is consistent across subgroups and not explained by differences in income, education, or insurance coverage.
PMCID: PMC3092472  PMID: 21572580
lung neoplasms; carcinoma; non-small-cell lung; neoplasm staging; tomography; emission-computed; healthcare disparities
18.  Lung cancer stage at diagnosis: Individual associations in the prospective VITamins and lifestyle (VITAL) cohort 
BMC Cancer  2011;11:228.
Lung cancer is the leading cause of cancer death in the United States. Identifying factors associated with stage of diagnosis can improve our understanding of biologic and behavioral pathways of lung cancer development and detection. We used data from a prospective cohort study to evaluate associations of demographic, health history, and health behaviors with early versus late stage at diagnosis of non-small cell lung cancer (NSCLC).
We calculated odds ratios (ORs) for the association of patient-level characteristics with advanced stage of diagnosis for NSCLC. The OR's were then adjusted for age, gender, race/ethnicity, smoking status, income, education, chronic obstructive pulmonary disease, and a comorbidity index.
We identified 612 cases of NSCLC among 77,719 adults, aged 50 to 76 years from Washington State recruited in 2000-2002, with followup through December 2007. In univariate analyses, subjects who quit smoking <10 years (OR 2.56, 95% CI 1.17 - 5.60) and were college graduates (OR 1.67, 95% CI, 1.00 - 2.76) had increased risks of being diagnosed with advanced stage NSCLC, compared to never smokers and non-college graduates, respectively. Receipt of sigmoidoscopy/colonoscopy, compared to no receipt, was associated with a decreased risk of advanced stage (OR 0.65, 95% CI, 0.43 - 0.99). The adjusted OR for receipt of sigmoidoscopy/colonoscopy was 0.55 (95% CI, 0.36 - 0.86). There was evidence that increasing the number of screening activities was associated with a decreased risk of advanced stage NSCLC (P for trend = 0.049).
Smoking status, education, and a screening activity were associated with stage at diagnosis of NSCLC. These results may guide future studies of the underlying mechanisms that influence how NSCLC is detected and diagnosed.
PMCID: PMC3129325  PMID: 21649915
19.  Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study 
Journal of Clinical Oncology  2010;28(9):1540-1546.
Lung cancer is the leading cause of cancer-related mortality among women. The role of hormone replacement therapy (HRT) in lung cancer development is unclear.
Patients and Methods
We evaluated a prospective cohort of 36,588 peri- and postmenopausal women aged 50 to 76 years from Washington State recruited in 2000 to 2002 (Vitamins and Lifestyle [VITAL] Study). Lung cancer cases (n = 344) were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis.
After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of estrogen plus progestin (E+P) use (HR = 1.27 for E+P use 1 to 9 years, 95% CI, 0.91 to 1.78; and HR = 1.48 for E+P use ≥ 10 years, 95% CI, 1.03 to 2.12; P for trend = .03). There was no association with duration of unopposed estrogen use. Duration of E+P use was associated with an advanced stage at diagnosis (P for trend = .03).
Use of E+P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer.
PMCID: PMC2849773  PMID: 20159813
20.  The validity of using ICD-9 codes and pharmacy records to identify patients with chronic obstructive pulmonary disease 
Administrative data is often used to identify patients with chronic obstructive pulmonary disease (COPD), yet the validity of this approach is unclear. We sought to develop a predictive model utilizing administrative data to accurately identify patients with COPD.
Sequential logistic regression models were constructed using 9573 patients with postbronchodilator spirometry at two Veterans Affairs medical centers (2003-2007). COPD was defined as: 1) FEV1/FVC <0.70, and 2) FEV1/FVC < lower limits of normal. Model inputs included age, outpatient or inpatient COPD-related ICD-9 codes, and the number of metered does inhalers (MDI) prescribed over the one year prior to and one year post spirometry. Model performance was assessed using standard criteria.
4564 of 9573 patients (47.7%) had an FEV1/FVC < 0.70. The presence of ≥1 outpatient COPD visit had a sensitivity of 76% and specificity of 67%; the AUC was 0.75 (95% CI 0.74-0.76). Adding the use of albuterol MDI increased the AUC of this model to 0.76 (95% CI 0.75-0.77) while the addition of ipratropium bromide MDI increased the AUC to 0.77 (95% CI 0.76-0.78). The best performing model included: ≥6 albuterol MDI, ≥3 ipratropium MDI, ≥1 outpatient ICD-9 code, ≥1 inpatient ICD-9 code, and age, achieving an AUC of 0.79 (95% CI 0.78-0.80).
Commonly used definitions of COPD in observational studies misclassify the majority of patients as having COPD. Using multiple diagnostic codes in combination with pharmacy data improves the ability to accurately identify patients with COPD.
PMCID: PMC3050695  PMID: 21324188
21.  Association of Non-Steroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study 
Lung cancer is the most common cause of cancer-related mortality. Smoking cessation is crucial to decrease risk but additional prevention modalities are needed. Use of non-steroidal anti-inflammatory drugs (NSAIDs) may be promising.
The study was a prospective cohort of 77,125 men and women aged 50–76 years from Washington State recruited in 2000–2002 (the VITAL study). Lung cancer cases were identified through the Seattle-Puget Sound SEER cancer registry during 5 years of follow-up. Hazard ratios (HRs) associated with 10 year average use of total NSAIDs (excluding low-dose aspirin) and specific categories of NSAIDs were calculated for total incident lung cancer and specific morphologies.
665 lung cancer cases were identified. After adjusting for smoking, age, gender, and acetaminophen use, there was a borderline-significant inverse trend with total NSAID use (>4.2 days/week over 10 years vs. none, HR 0.82, 95% CI, 0.64–1.04, P for trend 0.05). The association was strongest for adenocarcinoma (HR 0.59, 95% CI, 0.37–0.94, P for trend 0.01) and appeared to be limited to men (HR 0.66, 95% CI, 0.47–0.92, P for trend 0.01) and to long-term (≥ 10 years) former smokers (HR 0.65, 95% CI, 0.44–0.96, P for trend 0.04). There were no appreciable differences by NSAID type.
Total NSAID use was associated with a small reduced risk of lung cancer which was strongest for adenocarcinoma, men, and long-term former smokers. These findings are supported by known lung carcinogenesis mechanisms, and suggest that NSAIDS may be useful for chemoprevention.
PMCID: PMC2692934  PMID: 19293309
lung cancer; adenocarcinoma; non-steroidal anti-inflammatory drugs; cyclooxygenase-2; chemoprevention
22.  The Effects of Smoking Cessation on the Risk of Chronic Obstructive Pulmonary Disease Exacerbations 
Smoking cessation has been demonstrated to reduce the rate of loss of lung function and mortality among patients with mild to moderate chronic obstructive pulmonary disease (COPD). There is a paucity of evidence about the effects of smoking cessation on the risk of COPD exacerbations.
We sought to examine whether smoking status and the duration of abstinence from tobacco smoke is associated with a decreased risk of COPD exacerbations.
We assessed current smoking status and duration of smoking abstinence by self-report. Our primary outcome was either an inpatient or outpatient COPD exacerbation. We used Cox regression to estimate the risk of COPD exacerbation associated with smoking status and duration of smoking cessation.
We performed a cohort study of 23,971 veterans who were current and past smokers and had been seen in one of seven Department of Veterans Affairs (VA) primary care clinics throughout the US.
In comparison to current smokers, ex-smokers had a significantly reduced risk of COPD exacerbation after adjusting for age, comorbidity, markers of COPD severity and socio-economic status (adjusted HR 0.78, 95% CI 0.75–0.87). The magnitude of the reduced risk was dependent on the duration of smoking abstinence (adjusted HR: quit <1 year, 1.04; 95% CI 0.87–1.26; 1–5 years 0.93, 95% CI 0.79–1.08; 5–10 years 0.84, 95% CI 0.70–1.00; ≥10 years 0.65, 95% CI 0.58–0.74; linear trend <0.001).
Smoking cessation is associated with a reduced risk of COPD exacerbations, and the described reduction is dependent upon the duration of abstinence.
PMCID: PMC2659150  PMID: 19194768
chronic obstructive pulmonary disease; exacerbation; smoking cessation
23.  Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer 
Rationale: Lung cancer is the leading cause of cancer-related mortality in the United States. Although supplements are used by half the population, limited information is available about their specific effect on lung cancer risk.
Objectives: To explore the association of supplemental multivitamins, vitamin C, vitamin E, and folate with incident lung cancer.
Methods: Prospective cohort of 77,721 men and women aged 50–76 years from Washington State in the VITAL (VITamins And Lifestyle) study. Cases were identified through the Seattle–Puget Sound SEER (Surveillance, Epidemiology, and End Results) cancer registry.
Measurements and Main Results: Hazard ratios (HRs) for incident lung cancer according to 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. A total of 521 cases of lung cancer were identified. Adjusting for smoking, age, and sex, there was no inverse association with any supplement. Supplemental vitamin E was associated with a small increased risk of lung cancer (HR, 1.05 for every 100-mg/d increase in dose; 95% confidence interval [CI], 1.00–1.09; P = 0.033). This risk of supplemental vitamin E was largely confined to current smokers (HR, 1.11 for every 100-mg/d increase; 95% CI, 1.03–1.19; P < 0.01) and was greatest for non–small cell lung cancer (HR, 1.07 for every 100-mg/d increase; 95% CI, 1.02–1.12; P = 0.004).
Conclusions: Supplemental multivitamins, vitamin C, vitamin E, and folate were not associated with a decreased risk of lung cancer. Supplemental vitamin E was associated with a small increased risk. Patients should be counseled against using these supplements to prevent lung cancer.
PMCID: PMC2258445  PMID: 17989343
bronchial neoplasm; diet; dietary supplements; public health
24.  cis-9,10-Bis(bromo­meth­yl)-1,4,5,8-tetra­oxadeca­lin 
The title compound, C8H12Br2O4, is a bicyclic ketal in which the two six-membered rings are cis to one another and assume a double-chair conformation. A crystallographic twofold axis bisects the molecule.
PMCID: PMC2961570  PMID: 21202679
25.  Inhaled Corticosteroids and Risk of Lung Cancer among Patients with Chronic Obstructive Pulmonary Disease 
Rationale and Objectives: Lung cancer is a frequent cause of death among patients with chronic obstructive pulmonary disease (COPD). We examined whether the use of inhaled corticosteroids among patients with COPD was associated with a decreased risk of lung cancer.
Methods: We performed a cohort study of United States veterans enrolled in primary care clinics between December 1996 and May 2001. Participants had received treatment for, had an International Classification of Disease, 9th edition, diagnosis of, or a self-reported diagnosis of COPD. Patients with a history of lung cancer were excluded. To be exposed, patients must have been at least 80% adherent to inhaled corticosteroids. We used Cox regression models to estimate the risk of cancer and adjust for potential confounding factors.
Findings: We identified 10,474 patients with a median follow-up of 3.8 years. In comparison to nonusers of inhaled corticosteroids, adjusting for age, smoking status, smoking intensity, previous history of non–lung cancer malignancy, coexisting illnesses, and bronchodilator use, there was a dose-dependent decreased risk of lung cancer associated with inhaled corticosteroids (ICS dose < 1,200 μg/d: adjusted HR, 1.3; 95% confidence interval, 0.67–1.90; ICS dose ⩾ 1,200 μg/d: adjusted HR, 0.39; 95% confidence interval, 0.16–0.96). Changes in cohort definitions had minimal effects on the estimated risk. Analyses examining confounding by indication suggest biases in the opposite direction of the described effects.
Interpretation: Results suggest that inhaled corticosteroids may have a potential role in lung cancer prevention among patients with COPD. These initial findings require confirmation in separate and larger cohorts.
PMCID: PMC1899285  PMID: 17185647
chronic obstructive pulmonary disease; pharmacoepidemiology; lung cancer; adherence

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