Background The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of ...omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. Objective We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. Methods EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. Results The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. Conclusion Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.
Epidemiological studies of interstitial lung disease (ILD) are limited by small numbers and tertiary care bias. Investigators have leveraged the widespread use of electronic health records (EHRs) to ...overcome these limitations, but struggle to extract patient-level, longitudinal clinical data needed to address many important research questions. We hypothesized that we could automate longitudinal ILD cohort development using the EHR of a large, community-based healthcare system.
We applied a previously validated algorithm to the EHR of a community-based healthcare system to identify ILD cases between 2012-2020. We then extracted disease-specific characteristics and outcomes using fully automated data-extraction algorithms and natural language processing of selected free-text.
We identified a community cohort of 5,399 ILD patients (prevalence = 118 per 100,000). Pulmonary function tests (71%) and serologies (54%) were commonly used in the diagnostic evaluation, whereas lung biopsy was rare (5%). IPF was the most common ILD diagnosis (n = 972, 18%). Prednisone was the most commonly prescribed medication (911, 17%). Nintedanib and pirfenidone were rarely prescribed (n = 305, 5%). ILD patients were high-utilizers of inpatient (40%/year hospitalized) and outpatient care (80%/year with pulmonary visit), with sustained utilization throughout the post-diagnosis study period.
We demonstrated the feasibility of robustly characterizing a variety of patient-level utilization and health services outcomes in a community-based EHR cohort. This represents a substantial methodological improvement by alleviating traditional constraints on the accuracy and clinical resolution of such ILD cohorts; we believe this approach will make community-based ILD research more efficient, effective, and scalable.
Abstract Background EXCELS was a postmarketing commitment to the US Food and Drug Administration to assess long-term safety of omalizumab in an observational setting, focusing predominantly on ...malignancies. Objective To examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. Methods Cohort study of patients (≥12 years of age) with moderate-to-severe allergic asthma followed ≤5 years, treated with omalizumab (n = 5007) or not treated with omalizumab (n = 2829) at baseline. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATE), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, or unstable angina. A prespecified analysis for the endpoint of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. Results At baseline, cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus non-omalizumab cohorts (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1000 person-years PY) than non-omalizumab–treated patients (8.1 per 1000 PY). ATE rate per 1000 PY was 6.66 (101 patients/15,160 PY) for the omalizumab cohort and 4.64 (46 patients/9904 PY) for the non-omalizumab cohort. After controlling for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). Conclusion Results from this observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus non-omalizumab cohorts. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded (NCT00252135). Clinical implications Current asthma management guidelines should not be affected. However, health professionals should be aware of a possible association of omalizumab and serious cardiovascular/cerebrovascular events.
Abstract Background Prior research on the risk of depression in chronic obstructive pulmonary disease (COPD) has yielded conflicting results. Furthermore, we have an incomplete understanding of how ...much depression versus respiratory factors contributes to poor health-related quality of life. Methods Among 1202 adults with COPD and 302 demographically matched referents without COPD, depressive symptoms were assessed using the 15-item Geriatric Depression Score. We measured COPD severity using a multifaceted approach, including spirometry, dyspnea, and exercise capacity. We used the Airway Questionnaire 20 and the Physical Component Summary Score to assess respiratory-specific and overall physical quality of life, respectively. Results In multivariate analysis adjusting for potential confounders including sociodemographics and all examined comorbidities, COPD subjects were at higher risk for depressive symptoms (Geriatric Depression Score ≥6) than referents (odds ratio OR 3.6; 95% confidence interval CI, 2.1-6.1; P <.001). Stratifying COPD subjects by degree of obstruction on spirometry, all subgroups were at increased risk of depressive symptoms relative to referents ( P <.001 for all). In multivariate analysis controlling for COPD severity as well as sociodemographics and comorbidities, depressive symptoms were strongly associated with worse respiratory-specific quality of life (OR 3.6; 95% CI, 2.7-4.8; P <.001) and worse overall physical quality of life (OR 2.4; 95% CI, 1.8-3.2; P <.001). Conclusions Patients with COPD are at significantly higher risk of having depressive symptoms than referents. Such symptoms are strongly associated with worse respiratory-specific and overall physical health-related quality of life, even after taking COPD severity into account.
The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva ...samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.
Abstract Purpose Although chronic obstructive pulmonary disease (COPD) has a major impact on physical health, the specific impact of COPD on physical functional limitations has not been characterized ...clearly. We aimed to elucidate the physical functional limitations that are directly attributable to COPD compared to a matched referent group without the condition. Methods We used the Function, Living, Outcomes, and Work (FLOW) cohort study of adults with COPD (n=1202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery SPPB), submaximal exercise performance (Six Minute Walk Test SMWT), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multivariate analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Results COPD was associated with poorer lower extremity function (mean SPPB score decrement for COPD vs referent −1.0 points; 95% CI, −1.25 to −0.73 pts) and less distance walked during the SMWT (−334 feet; 95% CI, −384 to −282 ft). COPD also was associated with weaker muscle strength in every muscle group tested, including both the upper and lower extremities ( P <.0001 in all cases) and with a greater risk of self-reported functional limitation (OR 6.4; 95% CI, 3.7 to 10.9). Conclusions A broad array of physical functional limitations were specifically attributable to COPD. COPD affects a multitude of body systems remote from the lung.
Peak lung function and rate of decline predict future airflow obstruction and nonrespiratory comorbid conditions. Associations between lung function trajectories and emphysema have not been explored.
...Using data from the population-based CARDIA Study, we sought to describe the prevalence of visually ascertained emphysema at multiple time points and contextualize its development based upon participant’s adult life course measures of lung function. There were 3171 men and women enrolled at a mean age of 25 years, who underwent serial spirometric examinations through a mean age of 55 years. Trajectories for the change in percent-predicted forced expiratory volume in one second (FEV1) were determined by fitting a mixture model via maximum likelihood. Emphysema was visually identified on computed tomographic scans and its prevalence reported at mean ages of 40, 45, and 50 years.
We identified 5 trajectories describing peak and change in FEV1: “Preserved Ideal,” “Preserved Good,” “Preserved Impaired,” “Worsening,” and “Persistently Poor.” Ever smokers comprised part of all 5 trajectories. The prevalence of emphysema was 1.7% (n = 46; mean age of 40 years), 2.5% (n = 67; mean age of 45 years), and 7.1% (n = 189; mean age of 50 years). Of those with emphysema at a mean age of 50 years, 18.0% were never smokers. Worsening and poor lung health trajectories were associated with increased odds of future emphysema independent of chronic tobacco smoke exposure (odds ratio 5.06; confidence interval, 1.84-13.96; odds ratio 4.85; confidence interval, 1.43-16.44).
Lower peak and accelerated decline in FEV1 are risk factors for future emphysema independent of smoking status.
We examined the clinical utility of two multi-locus genetic risk scores (GRSs) previously validated in Europeans among persons of African (AFR; n = 2,089), Latino (LAT; n = 4,349) and East-Asian (EA; ...n = 4,804) ancestry. We used data from the GERA cohort (30-79 years old, 68 to 73% female). We utilized two GRSs with 12 and 51 SNPs, respectively, and the Framingham Risk Score (FRS) to estimate 10-year CHD risk. After a median 8.7 years of follow-up, 450 incident CHD events were documented (95 in AFR, 316 in LAT and 39 EA, respectively). In a model adjusting for principal components and risk factors, tertile 3 vs. tertile 1 of GRS_12 was associated with 1.86 (95% CI, 1.15-3.01), 1.52 (95% CI, 1.02-2.25) and 1.19 (95% CI, 0.77-1.83) increased hazard of CHD in AFR, LAT and EA, respectively. Inclusion of the GRSs in models containing the FRS did not increase the C-statistic but resulted in net overall reclassification of 10% of AFR, 7% LAT and EA and in reclassification of 13% of AFR and EA as well as 10% LAT in the intermediate FRS risk subset. Our results support the usefulness of incorporating genetic information into risk assessment for primary prevention among minority subjects in the U.S.
...characterization of rs12712142, which was annotated to the 3'UTR region of IL1RL1, showed that it introduces a new binding site for hsa-miR-452-5p, which is also significantly upregulated in ...airway epithelia samples from those with asthma compared with samples from healthy, nonatopic controls (see Figs E2 and E3 in this article's Online Repository at www.jacionline.org). Because variations across multiple genes within affected pathways could directly impact asthma phenotypes, we analyzed 2143 suggestive (P < 1 × 10−05) associations from non-Hispanic whites in GERA for gene-set and tissue enrichment. Collectively, these analyses replicated previously reported top asthma GWAS findings as well as increased the significance threshold for many of these associations, in addition to expanding the list of novel SNPs that are strongly associated with asthma risk. Because of differences in GWAS study design, imputation, and available SNP data, most genome-wide significant SNPs from the discovery GWAS were not well represented in EVE or GABRIEL, limiting the total number of SNPs for replication. ...although we present novel GWAS findings from racial/ethnic groups in addition to non-Hispanic whites, our ability to replicate associations from these and other populations was limited, due in part to the aforementioned reasons. ...previously unreported SNPs within the MHC II region of chromosome 6 and the IL1RL1/IL18R1 region of chromosome 2 are associated with asthma susceptibility in adults of non-Hispanic white ancestry, whereas novel SNPs in FOXRED2 and TXN2 are associated with asthma in Asians, and COL3A1 is associated with asthma in African Americans.
PDF
