COPD Cohort Research Articles

P110 Quantitative PCR-based detection and quantification of atypical bacteria at baseline and exacerbation of COPD

IntroductionAirway bacterial infections are associated with exacerbations of COPD. The potential role of atypical bacteria as a trigger for exacerbations is not well understood. Atypical bacteria such as Chlamydophila pneumoniae...

Six‐minute walk test in pulmonary rehabilitation: Do all patients need a practice test?

The six-minute walk test (6MWT) is widely used as an outcome measure in pulmonary rehabilitation programs (PRP). A learning effect for the test has been reported in COPD; however, limited data exist in patients with other respiratory diagnoses. The objectives of this study were to: (i) report the magnitude of change in 6MWD with test repetition in patients referred to an outpatient PRP, and (ii) compare the magnitude of change in 6MWD with test repetition in patients with COPD, interstitial lung disease (ILD), bronchiectasis and asthma. Retrospective study of 349 patients with stable COPD (n = 245), ILD (n = 21), bronchiectasis (n = 33) or asthma (n = 50) who performed two 6MWT at enrollment into a PRP. 6MWD increased in all groups on the second test (all P < 0.001). At least 80% of patients in each diagnostic group walked further on their second 6MWT. The magnitude of change (mean, 95% CI) was greater (P < 0.05) in the COPD (37 m, 95% CI: 33-41 m) and ILD (41 m, 95% CI: 27-55 m) cohorts compared with the bronchiectasis (22 m, 95% CI: 14-31 m) and asthma (19 m, 95% CI: 11-27 m) cohorts. Respiratory diagnosis influences the magnitude of the learning effect for the 6MWT. The findings support the recommendation of a practice 6MWT at baseline assessment in order to provide an accurate measure of the effects of rehabilitation on 6MWD.

Neutrophil Gelatinase-Associated Lipocalin: A Biomarker in COPD

<h3>Background</h3> Neutrophil gelatinase-associated lipocalin (NGAL) is an antimicrobial peptide that could be involved in the pathogenesis of COPD. This study aimed to measure the plasma levels of NGAL in a large cohort of patients with COPD and control subjects and examine the levels of NGAL by COPD characteristics. <h3>Methods</h3> The study included 402 patients with COPD and 229 control subjects aged 40 to 76 years from the Bergen COPD Cohort Study. All patients with COPD had an FEV₁/FVC ratio of < 0.7, an FEV₁ < 80% predicted, and a smoking history of ≥ 10 pack-years. Plasma levels of NGAL were determined by enzyme immunoassay. Linear regression models were fitted with NGAL as the outcome variable. Confounders examined were sex, age, smoking, Charlson comorbidity score, use of inhaled steroids, neutrophil cell count, plasma creatinine and ferritin, and C-reactive protein. <h3>Results</h3> Mean ± SD plasma concentrations of NGAL were 75.1 ± 31.8 ng/mL in patients with COPD and 56.5 ± 22.0 ng/mL in control subjects (<i>P</i> < .01). NGAL levels were bivariately associated with age, smoking, body composition, Charlson comorbidity score, neutrophil blood count, creatinine, and C-reactive protein but were significantly elevated in patients with COPD, even after adjustment for confounders. Frequent exacerbations and hypoxemia was associated with higher levels of NGAL, whereas increasing Global Initiative for Chronic Obstructive Lung Disease stage was associated with lower levels of NGAL among patients with COPD. <h3>Conclusions</h3> Plasma levels of NGAL were significantly higher in patients with COPD compared with control subjects. NGAL was related to important COPD characteristics.

Characterisation of COPD heterogeneity in the ECLIPSE cohort

BackgroundChronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).MethodsWe studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.ResultsCOPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.ConclusionsThe clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.

Interactions Between COPD and Outcomes After Percutaneous Coronary Intervention

COPD is common in patients undergoing percutaneous coronary intervention (PCI), but its association with outcomes following PCI has received only limited study. The effects of COPD severity on outcomes after PCI are not known. We conducted a retrospective cross-sectional analysis of prospectively acquired data in 14,346 consecutive patients enrolled in the Mayo Clinic PCI registry. Patients with COPD were identified by International Classification of Diseases, 9th edition, coding and pulmonary function test (PFT) results. Outcomes of COPD vs non-COPD cohorts were compared. The COPD group included 2,001 patients (72% men) aged 70 +/- 10 years, and the non-COPD group included 12,345 patients (70% men) aged 66 +/- 12 years. In the follow-up period after PCI (median, 4.1 years; interquartile range, 1.9-7.0 years), the patients with COPD experienced a significantly higher incidence of all-cause mortality (P < .0001), cardiac mortality (P < .0001), and myocardial infarction (MI) (P < .0001) than the patients without COPD. Additionally, severity of COPD was associated with increased mortality after PCI (P < .0001). In a multivariate analysis, COPD presence and severity remained significant risk factors for mortality (P < .0001), cardiac mortality (P < .0001), and occurrence of MI after PCI (P < .0001). COPD is associated with significantly increased overall long-term mortality, cardiac mortality, and occurrence of MI in patients undergoing PCI. Increasing severity of COPD as measured by PFT is associated with decreased survival after PCI. Screening for COPD in patients undergoing PCI could contribute importantly to risk stratification, identifying patients needing closer follow-up and optimizing targeted therapeutic interventions.

General practitioners’ adherence to the COPD GOLD guidelines: baseline data from the Swiss COPD Cohort Study

General practitioners’ adherence to the COPD GOLD guidelines: baseline data from the Swiss COPD Cohort Study

Measurement of COPD Severity Using a Survey-Based Score: Validation in a Clinically and Physiologically Characterized Cohort

A comprehensive survey-based COPD severity score has usefulness for epidemiologic and health outcomes research. We previously developed and validated the survey-based COPD Severity Score without using lung function or other physiologic measurements. In this study, we aimed to further validate the severity score in a different COPD cohort and using a combination of patient-reported and objective physiologic measurements. Using data from the Function, Living, Outcomes, and Work cohort study of COPD, we evaluated the concurrent and predictive validity of the COPD Severity Score among 1,202 subjects. The survey instrument is a 35-point score based on symptoms, medication and oxygen use, and prior hospitalization or intubation for COPD. Subjects were systemically assessed using structured telephone survey, spirometry, and 6-min walk testing. We found evidence to support concurrent validity of the score. Higher COPD Severity Score values were associated with poorer FEV(1) (r = -0.38), FEV(1)% predicted (r = -0.40), Body mass, Obstruction, Dyspnea, Exercise Index (r = 0.57), and distance walked in 6 min (r = -0.43) (P < .0001 in all cases). Greater COPD severity was also related to poorer generic physical health status (r = -0.49) and disease-specific health-related quality of life (r = 0.57) (P < .0001). The score also demonstrated predictive validity. It was also associated with a greater prospective risk of acute exacerbation of COPD defined as ED visits (hazard ratio [HR], 1.31; 95% CI, 1.24-1.39), hospitalizations (HR, 1.59; 95% CI, 1.44-1.75), and either measure of hospital-based care for COPD (HR, 1.34; 95% CI, 1.26-1.41) (P < .0001 in all cases). The COPD Severity Score is a valid survey-based measure of disease-specific severity, both in terms of concurrent and predictive validity. The score is a psychometrically sound instrument for use in epidemiologic and outcomes research in COPD.

ICE COLD ERIC – International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts – Study protocol for an international COPD cohort study

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4.Methods/DesignWe will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years.DiscussionDespite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis.Trial registrationClinicalTrials.gov Archive NCT00706602

Medication adherence and persistence in the last year of life in COPD patients

To examine medication adherence and persistence among COPD patients during their last year of life. National VA databases were used to identify patients who had COPD and died between 1999 and 2003. We examined use of inhaled corticosteroids (ICS), long acting beta(2) agonists (LABA), methylxanthines (MTX), and anticholinergics (AC), alone and in combination. Medication possession ratios (MPR) were compared between regimens by quarterly periods using General Estimating Equations (GEE). Medication persistence was examined in monotherapy users with Kaplan-Meier survival analysis and extended Cox proportional hazard models. Only half of the identified patients in the COPD cohort (5913 of 11,376) used any medications. Among 5913 patients, overall mean (SD) MPR was 0.44 (0.32) during the last year of life. A positive linear trend in MPR was observed across quarterly periods in AC users (beta=0.014, p<0.0001), and was highest for MTX users (beta=0.11, p<0.0001). Of 3436 on monotherapy only, 40% discontinued medication within 30 days, and 70% discontinued within 90 days. MTX users were less likely to discontinue (HR=0.714, p=0.012) than reference (AC) group. COPD patients in their last year of life tended to use respiratory medications sporadically. Further research is needed to qualify whether minor differences in MPR between regimens reflect behavioral differences related to regimen or reflect refill policy and MPR calculation technique.

A 20-Year Follow-Up of a Population Study-Based COPD Cohort-Report from the Obstructive Lung Disease in Northern Sweden Studies

Mortality and other long-term outcomes of COPD from epidemiological studies of cohorts based on the general population are still rare. In contrast, data from follow-ups of patients from hospitals and general practices are more common and demonstrate often a 5-year mortality of about 50% and even higher. The aim was to study 20-year outcomes, mainly mortality, in a COPD cohort derived from a population study. The Obstructive Lung Disease in Northern Sweden (OLIN) Study's first postal survey was performed in 1985, and 5698 subjects (86%) responded. A stratified sample of symptomatic subjects and controls was invited to clinical examinations including lung function tests in 1986, 1506 (91%) of the invited participated and 266 subjects fulfilled the GOLD criteria of COPD. All alive and possible to trace had participated at least at two follow-up examinations. Of the 266 subjects with COPD 46% were still alive after 20 years. The proportion of survived among subjects with severe and very severe COPD at entry was 19%. Death was significantly related to age, male sex, disease severity and concomitant ischemic heart disease or cardiac failure at entry. Socioeconomic status (manual workers) was significant in the univariate analysis, but failed to reach statistical significance in the multivariate model. The annual decline in FEV1 among survivors was low to normal. Long-term follow-ups of subjects with COPD derived from population studies provide data reflecting the course of COPD in society better than follow-ups of hospital recruited patients, who represent the top of the iceberg. Surprisingly many with severe COPD were still alive after 20 years.

Coded Cause of Death and Timing of COPD Diagnosis

The aims of this study were to characterize causes of death among veterans with COPD using multiple cause of death coding, and to examine whether causes of death differed according to timing of COPD diagnosis. Veterans with COPD who died during a five-year follow-up period were identified from national VA databases linked to National Death Index files. Primary, secondary, underlying, and all-coded causes of death were compared between recent and preexistent COPD cohorts using proportional mortality ratios (PMRs), which compares proportion dying from specific causes as opposed to absolute risk of death. Of 26,357 decedents, 7,729 were categorized preexistent and 18,628 were recent COPD cases. Unspecified COPD was listed as underlying cause of death in a significantly greater proportion of preexistent COPD cases compared to recent cases, 20% vs 10%, PMR = 2.0 (95% CI: 1.9–2.1). A relatively higher proportion of recently diagnosed cases died from lung/bronchus, prostate, and site-unspecified cancers. Respiratory failure (J969) was rarely coded as an underlying or primary cause (< 1%), but was a second-code cause of death in 9% of recent and 12% of preexistent cases. Differences in coded causes of death between patients with a recent diagnosis of COPD compared to a preexistent diagnosis of COPD suggests that there is either coded cause-related bias or true differences in cause of death related to length of time with diagnosis. Thus, methods used to identify cohorts of COPD patients, i.e., incidence versus prevalence-based approaches, and coded cause of death can affect estimates of cause-specific mortality.

Particulate air pollution and survival in a COPD cohort

BackgroundSeveral studies have shown cross-sectional associations between long term exposure to particulate air pollution and survival in general population or convenience cohorts. Less is known about susceptibility, or year to year changes in exposure. We investigated whether particles were associated with survival in a cohort of persons with COPD in 34 US cities, eliminating the usual cross-sectional exposure and treating PM10 as a within city time varying exposure.MethodsUsing hospital discharge data, we constructed a cohort of persons discharged alive with chronic obstructive pulmonary disease using Medicare data between 1985 and 1999. 12-month averages of PM10 were merged to the individual annual follow up in each city. We applied Cox's proportional hazard regression model in each city, with adjustment for individual risk factors.ResultsWe found significant associations in the survival analyses for single year and multiple lag exposures, with a hazard ratio for mortality for an increase of 10 μg/m3 PM10 over the previous 4 years of 1.22 (95% CI: 1.17–1.27).ConclusionPersons discharged alive for COPD have substantial mortality risks associated with exposure to particles. The risk is evident for exposure in the previous year, and higher in a 4 year distributed lag model. These risks are significantly greater than seen in time series analyses.

Increased Systemic Inflammation Is a Risk Factor for COPD Exacerbations

COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation. To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD. The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-alpha, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined. Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations. This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.

β2-Adrenergic Receptor Genetic Polymorphisms and Short-term Bronchodilator Responses in Patients With COPD

COPD is characterized by a persistent airflow limitation that is not fully reversible; thus, the reversibility of airflow limitations in response to a bronchodilator is an important component of COPD. Several studies have established that two common nonsynonymous polymorphisms in the beta2-adrenergic receptor gene (ADRB2), Arg16Gly and Gln27Glu, have important effects in modulating responses to beta2-agonists; however, the effects of these polymorphisms on responses to beta2-agonists in patients with COPD is unknown. To examine whether different genotypes at these two polymorphisms are related to differential responses to inhaled beta2-agonists in patients with COPD. A total of 246 patients with COPD who were participants in a longitudinal study of COPD (ie, the Hokkaido COPD cohort study) were studied. We compared short-term bronchodilator responses (BDRs) to salbutamol according to ADRB2 genotypes at codons 16 and 27. The presence of the Arg16 allele was associated with lower BDRs to beta2-agonist inhalation. The mean (+/-SD) log (postbronchodilator FEV1-prebronchodilator FEV1) values of Gly16 homozygotes (n=65), Arg16Gly16 heterozygotes (n=106), and Arg16 homozygotes (n=75) were 2.19+/-0.43, 2.09+/-0.42, and 2.01+/-0.42, respectively (p<0.05). The genetic effects of the Arg16Gly polymorphism were independent of the severity of airflow limitation, age, and smoking status. The most common Arg16-Gln27 haplotype was also significantly associated with decreased BDRs to salbutamol (p<0.01). The genetic effects of ADRB2 gene polymorphisms may explain some of the variability in response to therapeutic doses of a short-acting beta2-agonists in patients with COPD.

THE EPIDEMIOLOGY OF PNEUMONIA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): A GENERAL PRACTICE RESEARCH DATABASE (GPRD) STUDY

PURPOSE: Pneumonia is a common, serious and potentially life-threatening disease, yet its natural history in COPD patients is not well studied in population-based cohorts. We designed a study in the General Practice Research Database (GPRD), an automated medical records database representative of the UK population, to (1) quantify the incidence of community-acquired pneumonia (CAP) in a COPD cohort from 1996 to 2005, and (2) evaluate risk factors for CAP.

Policy Forum: The North Carolina System of Emergency Medical Services

**Introduction:** COPD is widely underdiagnosed worldwide; there is a drive to identify and treat patients earlier. Diagnostic spirometry is not widely available in many countries. The lung monitor is a simple screening test which measures FEV1/FEV6 and could be used as a screening step in primary care to identify patients suitable for spirometry referral. **Aims & objectives:** To assess performance of a simple post bronchodilator (postBD) COPD screener device compared to postBD quality diagnostic spirometry. **Methods:** We conducted a nested case-control study within the Birmingham COPD Cohort study. Patients with chronic respiratory symptoms at the final visit received postBD lung function assessment with the Vitalograph lung monitor (Index) followed by the nddEasy One spirometer (Reference). Cases were defined using the lower limit of normal (LLN - GLI), based on gold standard spirometry data. Correlation, agreement and discrimination (*c* statistic) was calculated. **Results:** 546 patients had reference and index test data. Reference and index tests were highly correlated for FEV1 (r=0.97; p\<0.001) and FEV6(screener) with FVC (spirometry)(r= 0.91; p\<0.001). 325 (59.5%) patients had airflow obstruction according to the reference test. The index test showed good discrimination (C=0.92; 95% CI 0.89, 0.94). Using the LLN as the cut-off, the index test had only 32.9% sensitivity (95% CI 27.8%, 38.3%) but 98.6% specificity (95% CI 96.1%, 99.7%); (PPV=97.3%, NPV=50.0%). **Conclusions:** Excellent correlation was observed between the postBD lung monitor and diagnostic spirometry, however the optimum cut-off for the lung monitor should be identified as use of the LLN cut-off has low sensitivity.

Applicability of American and European Spirometry Repeatability Criteria to Korean Adults

Background: The objective of this study was to evaluate the clinical applicability of the repeatability criteria recommended by the American Thoracic Society/European Respiratory Society (ATS/ERS) spirometry guidelines and to determine which factors affect the repeatability of spirometry in Korean adults. Methods: We reviewed the spirometry data of 4,663 Korean adults from the Korean National Health and Nutritional Examination Survey (KNHANES) Chronic Obstructive Pulmonary Disease Cohort (COPD cohort) and the Community-based Cohort Study VI-Fishing village/Islands (community cohort). We measured the anthropometric factors and differences between the highest and second-highest FVC (dFVC) and () from prebronchodilator spirometry. Analyses included the distribution of dFVC and , comparison of the values meeting the 1994 ATS repeatability criteria with the values meeting the 2005 ATS/ERS repeatability criteria, and the performance of linear regression for evaluating the influence of subject characteristics and the change of criteria on the spiro-metric variability. Results: About 95% of subjects were able to reproduce FVC and within 150 ml. The KNHANES based on the 1994 ATS guidelines showed poorer repeatability than the COPD cohort and community cohort based on the 2005 ATS/ERS guidelines. Demographic and anthropometric factors had little effect on repeatability, explaining only 0.5 to 3%. Conclusion: We conclude that the new spirometry repeatability criteria recommended by the 2005 ATS/ERS guidelines is also applicable to Korean adults. The repeatability of spirometry depends little on individual characteristics when an experienced technician performs testing. Therefore, we suggest that sustained efforts for public awareness of new repeatability criteria, quality control of spirograms, and education of personnel are needed for reliable spirometric results.

How Viral Infections Cause Exacerbation of Airway Diseases

Exacerbations of asthma and COPD are major causes of morbidity, mortality, and health-care costs. Over the last decade, studies using new molecular diagnostic techniques have established that respiratory viruses are a major cause of exacerbations of both asthma and COPD. The most prevalent viruses detected during exacerbations are the rhinoviruses. Despite the burden of disease associated with exacerbations, little is known about the mechanisms of virus-induced exacerbations of airway diseases. Exacerbations are associated with increased airway inflammation in patients with both asthma and COPD, but many questions remain unanswered regarding the key inflammatory cells and mediators involved. Identifying the key inflammatory mediators involved in exacerbations holds the promise of developing diagnostic and prognostic markers of exacerbation. In addition, such studies can identify new therapeutic targets for the development of novel drugs for the prevention and treatment of exacerbations.

Microarray Data-Based Prioritization of Chronic Obstructive Pulmonary Disease Susceptibility Genes

One limitation of genome-wide linkage screens aiming to identify disease-susceptibility genes is the resolution at which they define individual candidates. Fine mapping of linked loci can often be laborious, protracted, and poorly directed. We reasoned that an integrative genomics approach could help to expedite candidate gene identification. We tested this hypothesis by prioritizing genes within three linkage regions (chromosomes 2q33-36, 8pter-22, and 12p13-12) previously identified in the Boston Early-Onset COPD cohort (1), using two independent microarray data sets. Genes within previously defined linkage regions were identified using Golden Path (University of California Santa Cruz, http://genome.ucsc.edu), and associated probes were assigned using NetAffx (Affymetrix, Santa Clara, CA). Probe sets were filtered by sequence verification using The Lung Transcriptome (http://lungtranscriptome.bwh.harvard.edu). The first microarray data set studied consists of whole lung tissue samples derived from 20 patients who had undergone lung volume reduction surgery with severe emphysema and from 14 control subjects with mild to moderate obstruction (2). The second data set consists of whole lung tissue samples (uninvolved margin) derived from 31 patients undergoing surgery for solitary pulmonary nodules, with varying degrees of airflow obstruction (FEV1% predicted: mean, 72; range, 10–133), and has not been previously described. Signal intensities were derived using both MAS5 and RMA algorithms. Unsupervised clustering with the nonparametric bootstrap was applied to check for undesirable and unanticipated structure or associations among the samples. Pearson and Spearman correlations were used to test for significant associations between gene expression and continuous phenotypic variables (e.g., TLC, FEV1, FVC, FEV1/FVC, DlCO, FEF25–75, smoking history). All analysis methods were exhaustively repeated for each gene/probe set and each data set. For each gene/probe set, analysis results were summarized where data implicated an association between gene expression and the disease variable. Finally, genes were rank-prioritized based upon their frequency of significant association. A number of genes within each locus were repeatedly associated with multiple phenotypic variables in each data set. As has been previously noted, there was limited consistency between data sets, which in this case may be due to distinctions in patient populations and/or technical limitations. However, this approach consistently identified a small number of genes, including the recently implicated candidate susceptibility gene SERPINE2, as targets for further study. We believe this provides a rational approach that is applicable to many diseases and model systems for which data may already exist. However, further investigation is necessary to assert causation between prioritized candidates and the phenotype being investigated.

Estimating the Risk for Alpha-1 Antitrypsin Deficiency among COPD Patients: Evidence Supporting Targeted Screening

Alpha-1 antitrypsin deficiency is known as a significant genetic risk factor for COPD for carriers of phenotype PIMZ, and for phenotypes PIZZ and PISZ. Genetic epidemiological studies for alpha-1 antitrypsin deficiency conducted by others on both COPD patients and concurrent non-COPD controls were used to estimate the risk factors for all six phenotypic classes (namely, the normal phenotype PIMM, and the 5 deficiency allele phenotypes: PIMS, PIMZ, PISS, PISZ, and PIZZ). Studies on alpha-1 antitrypsin deficiency in white (Caucasian) COPD and non-COPD populations in 6 countries were combined to obtain estimates of the prevalence of the PIS and PIZ deficiency alleles in the combined COPD and non-COPD cohorts. The odds ratios for each of the six phenotypic classes of alpha-1 antitrypsin deficiency were calculated for a hypothetical population of 19.3 million white COPD patients in the United States of America. This approach demonstrated that 1,829,673 alpha-1 antitrypsin deficiency patients would be detected by testing 19.3 million white COPD patients and 536,033 in white non-COPD concurrent controls. The odds ratios for each of the phenotypic classes among white COPD patients demonstrate highly significant decreases in the normal phenotype PIMM, no significant change in the PIMS and PISS deficiency phenotypes, but highly significant increases in the prevalences of the PIMZ, PISZ, and PIZZ deficiency phenotypes. The result of the present study supports the concept of targeted screening for alpha-1 antitrypsin deficiency in countries with large populations of white (Caucasian) COPD patients.