Attitudes, Knowledge, and Risk Perceptions of Patients who Received Elective Genomic Testing as a Clinical Service.

BACKGROUND: Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients. METHODS: After web-based education, patients who enrolled in an EGT program at a rural nonprofit healthcare system completed a survey that assessed attitudes, knowledge, and risk perceptions. RESULTS: From August 2020 to April 2022, 5,920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person, but more often rated their risk for a heart attack as higher rather than lower than the average person (all p<0.001). CONCLUSION: Patients pursued EGT because of the utility expectations, but often misunderstood the test's capabilities.

The Association of Race, Ethnicity, and Insurance Status with the Visual Acuity of Retinoblastoma Survivors in the IRIS® Registry.

PURPOSE: To identify sociodemographic factors associated with the visual outcomes of retinoblastoma survivors. METHODS: Retrospective cohort study using a US-based clinical data registry. All individuals < 18 years of age with a history of retinoblastoma in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013-12/31/2020). The primary outcome was visual acuity below the threshold for legal blindness (20/200 or worse) in at least one eye. Multivariable logistic regression was used to evaluate the association between visual outcomes and age, sex, laterality, race, ethnicity, type of insurance, and geographic location. RESULTS: This analysis included 1545 children with a history of retinoblastoma. The median length of follow-up was 4.1 years (IQR, 2.2-5.9 years) and the median age at most recent clinical visit was 12 years (IQR, 8-16 years). Retinoblastoma was unilateral in 54% of cases. Poor vision in at least one eye was identified in 78% of all children and poor vision in both eyes in 17% of those with bilateral disease. Poor visual outcomes were associated with unilateral diagnosis (OR, 1.55; 95% CI,1.13-2.12; p = .007), Black race (OR, 2.03; 95% CI, 1.19-3.47; p = .010), Hispanic ethnicity (OR, 1.65; 95% CI, 1.16-2.37; p = .006), and non-private insurance (OR, 1.47; 95% CI, 1.02-2.10; p = .037). CONCLUSIONS: Poor visual outcomes appear to be more common among Black, Hispanic, and publicly insured children with a history of retinoblastoma, raising concerns regarding healthcare inequities. Primary care physicians should ensure that young children receive red reflex testing during routine visits and consider retinoblastoma in the differential diagnosis of abnormal eye exams.

Smaller Differences in the Comparative Effectiveness of Biologics in Reducing Asthma-Related Hospitalizations Compared With Overall Exacerbations.

BACKGROUND: Evidence on the comparative effectiveness of respiratory biologics remains sparse. OBJECTIVE: We sought to evaluate the comparative effectiveness of omalizumab, mepolizumab, benralizumab, and dupilumab in a matched retrospective cohort of patients with asthma. METHODS: We identified patients with asthma aged ≥18 years who were incident users of these biologics between November 1, 2018, and June 30, 2023, in administrative claims data from the Food and Drug Administration's Sentinel System and Merative MarketScan Commercial Database. We compared asthma-related exacerbations and hospitalizations in the 12 months since biologic prescription in pairwise comparisons of propensity score-matched cohorts. Covariates used in matching included age, sex, allergic comorbidities, baseline asthma medications use, and the Charlson Comorbidity Index. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using negative binomial regression models. RESULTS: A total of 893 patients on mepolizumab, 1300 on benralizumab, 1170 on omalizumab, and 1863 on dupilumab were identified. The average age was 55 years, and two-thirds of the participants were female. At baseline, over 80% of these individuals had an active prescription for an inhaled corticosteroid. Almost half of patients on dupilumab had concomitant nasal polyposis compared with 6% to 13% of patients on the other biologics. Covariates were balanced after matching. In matched analyses, dupilumab was associated with the lowest incidence of exacerbations over the follow-up period (vs dupilumab): mepolizumab (IRR: 1.36; 95% CI: 1.12, 1.64), omalizumab (IRR: 1.33; 95% CI: 1.13, 1.58), benralizumab (IRR: 1.19; 95% CI: 1.00, 1.41). For exacerbations leading to hospitalizations, benralizumab and mepolizumab were associated with the lowest incidence of hospitalizations, and the greatest difference was between mepolizumab versus dupilumab (IRR: 0.76; 95% CI: 0.56, 1.03). CONCLUSIONS: Dupilumab was associated with the lowest incidence of overall exacerbations, and mepolizumab with the lowest incidence of asthma hospitalizations in this administrative claims-based cohort of individuals with asthma. Despite matching propensity scores, residual confounding, such as baseline eosinophil count, may explain some of these findings.

Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study.

Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

Machine Learning Prediction of Treatment Response to Inhaled Corticosteroids in Asthma.

BACKGROUND: Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma. METHODS: The subjects included asthma patients of European ancestry (n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest. RESULTS: The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67-0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70-0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma (TPSAB1, FBXL16), asthma symptoms and severity (ABCA7, CNN2, PTRN3, and BSG/CD147), airway remodeling (ELANE, FSTL3), mucin production (GAL3ST), leukotriene synthesis (GPX4), allergic asthma (ZFPM1, SBNO2), and others. CONCLUSIONS: An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction.

GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Clinical impact of preemptive pharmacogenomic testing on antiplatelet therapy in a real-world setting.

CYP2C19 genotyping to guide antiplatelet therapy after patients develop acute coronary syndromes (ACS) or require percutaneous coronary interventions (PCIs) reduces the likelihood of major adverse cardiovascular events (MACE). Evidence about the impact of preemptive testing, where genotyping occurs while patients are healthy, is lacking. In patients initiating antiplatelet therapy for ACS or PCI, we compared medical records data from 67 patients who received CYP2C19 genotyping preemptively (results >7 days before need), against medical records data from 67 propensity score-matched patients who received early genotyping (results within 7 days of need). We also examined data from 140 patients who received late genotyping (results >7 days after need). We compared the impact of genotyping approaches on medication selections, specialty visits, MACE and bleeding events over 1 year. Patients with CYP2C19 loss-of-function alleles were less likely to be initiated on clopidogrel if they received preemptive rather than early or late genotyping (18.2%, 66.7%, and 73.2% respectively, p = 0.001). No differences were observed by genotyping approach in the number of specialty visits or likelihood of MACE or bleeding events (all p > 0.21). Preemptive genotyping had a strong impact on initial antiplatelet selection and a comparable impact on patient outcomes and healthcare utilization, compared to genotyping ordered after a need for antiplatelet therapy had been identified.

Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10-14) and among males (p = 1.0 × 10-9), but the signal was not genome-wide significant among females (p = 6.4 × 10-6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10-8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10-7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10-7) than former smokers (p = 7.5 × 10-3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10-8) and current smokers (p = 1.7 × 10-7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Gaps in the Vision Screening Pathway for School-Aged US Children.

This cross-sectional study uses a nationally representative survey of the US pediatric population to identify gaps in the vision screening pathway.

Antibiotic Treatment and Health Care Use in Children and Adolescents With Conjunctivitis.

This cohort study examines ambulatory care revisits and same-day topical antibiotic prescription in insured patients with acute infectious conjunctivitis.