Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort

Abstract: Purpose: We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)–associated variants (PRS313) and other, nongenetic risk factors. Methods: Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results: In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40–1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions: The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population

Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort

Purpose: We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)–associated variants (PRS313) and other, nongenetic risk factors. Methods: Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. Results: In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40–1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. Conclusions: The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population

Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease:a cross-sectional analysis of ten population-based studies

Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001). Interpretation: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity. Funding: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Prevalence of Asthma and COPD and Blood Eosinophil Count in a Middle-Aged Belgian Population

Various phenotypes exist in asthma and Chronic Obstructive Pulmonary Disease (COPD). These are important to identify in order to guide treatment decisions. We aim to investigate the prevalence and clinical characteristics of obstructive airway diseases in the middle-aged population. We estimated the prevalence of COPD and/or asthma in the Asklepios cohort study (Belgium), using information from the third European Community Respiratory Health Survey (ECRHS3), medical records, and spirometry. Respiratory symptoms, respiratory medication, and current disease status distinguished clinical from sub-clinical cases. In addition, we compared the blood eosinophil count/&micro;L (median [IQR]) between cases and controls. Of the 2221 participants (mean age 56.1 &plusmn; 5.9 years; 48.7% males), 138 (6.2%) participants had clinical current asthma, 22 (1.0%) participants had sub-clinical ever asthma, 102 (4.6%) had sub-clinical spirometry-defined COPD, 104 (4.6%) participants had clinical spirometry-confirmed COPD, and 11 (0.5%) had asthma and COPD overlap (ACO). Clinical current asthma (160.0 [110.0&ndash;250.0]), sub-clinical ever asthma (170.0 [110.0&ndash;230.0]), and clinical COPD (160.0 [110.0&ndash;220.0])&mdash;but less sub-clinical COPD (140.0 [90.0&ndash;210.0])&mdash;had higher eosinophil counts, compared to controls (130.0 [80.0&ndash;200.0]). We conclude that obstructive airway diseases are prevalent in the middle-aged Asklepios cohort. Moreover, the systemic eosinophil count is increased in clinical COPD cases, and in asthma cases regardless of clinical remission

Frailty transitions in older persons with lung function impairment: a population-based study

BACKGROUND: The ageing population and its burden on health-care systems warrant early detection of patients at risk of functional decline and mortality. We aimed to assess frailty transitions and its accuracy for mortality prediction in subjects with impaired spirometry (Preserved Ratio Impaired Spirometry [PRISm] or Chronic Obstructive Pulmonary Disease [COPD]). METHODS: In participants from the population-based Rotterdam Study (mean age 69.1±8.9 years), we examined whether PRISm (Forced Expiratory Volume in 1 second [FEV1]/Forced Vital Capacity [FVC]≥70% and FEV1<80%) or COPD (FEV1/FVC<70%) affected frailty transitions (progression/recovery between frailty states [robust, prefrailty and frailty], lost to follow-up or death) using age-, sex- and smoking state-adjusted multinomial regression models yielding odd's ratios (OR). Second, we assessed diagnostic accuracy of frailty score for predicting mortality in subjects with COPD using c-statistics. RESULTS: Compared to subjects with normal spirometry, subjects with PRISm were more likely to transit from robust (OR 2.2[1.2-4.2], p<0.05) or prefrailty (OR 2.6[1.3-5.5], p<0.01) towards frailty. Subjects with PRISm (OR 0.4[0.2-0.8], p<0.05) and COPD (OR 0.6[0.4-1.0], NS) were less likely to recover from their frail state, and were more likely to progress from any frailty state towards death (OR between 1.1 and 2.8, p<0.01). Accuracy for predicting mortality in subjects with COPD significantly improved when adding frailty score to age, sex and smoking status (90.5[82.3-89.8] vs 77.9[67.2-88.6], p<0.05). CONCLUSION: Participants with PRISm or COPD more often developed frailty with poor reversibility. Assessing physical frailty improved risk stratification for subjects with impaired spirometry for predicting increased life years

Blood eosinophil level and lung function trajectories : cross-sectional and longitudinal studies in European cohorts

Background: Elevated blood eosinophils have been associated with lower lung function and are believed to be associated with an accelerated lung function decline. Method: Blood eosinophils were measured in four cohorts:  &lt;45 years old cohort within the Vlagtwedde-Vlaardingen (V&amp;V) study,  the Uppsala cohort of the European Community Respiratory Health Survey (ECRHS-Uppsala ; &lt;45 years),  ≥45 years cohort within the V&amp;V study and  the Rotterdam study (≥45 years). Blood eosinophils at baseline were classified as normal (&lt;300 cells/μL) or elevated (≥300 cells/μL). Lung function was measured at baseline and follow-up with spirometry: forced exhaled volume during the first second (FEV1), vital capacity (VC) and their ratio FEV1/VC. The association between blood eosinophils and lung function was tested cross-sectionally using linear regression and longitudinally using a mixed model, both adjusted for age, sex, height, pack-years smoking and smoking status. Stratified analyses were done for asthma. Results: Elevated blood eosinophils associated to lower FEV1 (regression coefficient -149mL (95% Confidence Interval: -191; -107), VC (-124mL (-169; -78)) and FEV1/VC (-1.3% (-1.9; -0.7)) at baseline in the two &lt;45 years cohorts, and to lower FEV1 (-79mL (-116; -41)) and FEV1/VC (-1.8% (-2.6; -1.0)) in the two ≥45 years cohorts. Longitudinally, elevated compared to normal blood eosinophils were associated with an excess decline in FEV1 (-5.7mL/year (-11.1; -0.4), V&amp;V &lt;45 years) and VC (-12mL/year (-23.6; -0.9), ECRHS-Uppsala) only in asthmatics. Conclusion: Elevated blood eosinophils are associated with lower lung function in the general population and with an accelerated lung function decline among asthmatics