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Background: Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays., Methods and Findings: For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation., Conclusions: Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF., Trial Registration: Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PK and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose.

Early detection of atrial fibrillation (AF) enables initiation of anticoagulation and early rhythm control therapy to reduce stroke, cardiovascular death, and heart failure. In a cross-sectional, observational study, we aimed to identify a combination of circulating biomolecules reflecting different biological processes to detect prevalent AF in patients with cardiovascular conditions presenting to hospital. Twelve biomarkers identified by reviewing literature and patents were quantified on a high-precision, high-throughput platform in 1485 consecutive patients with cardiovascular conditions (median age 69 years [Q1, Q3 60, 78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. Logistic regression with backward elimination and a neural network approach considering 7 key clinical characteristics and 12 biomarker concentrations were applied to a randomly sampled discovery cohort (n = 933) and validated in the remaining patients (n = 552). In addition to age, sex, and body mass index (BMI), BMP10, ANGPT2, and FGF23 identified patients with prevalent AF (AUC 0.743 [95% CI 0.712, 0.775]). These circulating biomolecules represent distinct pathways associated with atrial cardiomyopathy and AF. Neural networks identified the same variables as the regression-based approach. The validation using regression yielded an AUC of 0.719 (95% CI 0.677, 0.762), corroborated using deep neural networks (AUC 0.784 [95% CI 0.745, 0.822]). Age, sex, BMI and three circulating biomolecules (BMP10, ANGPT2, FGF23) are associated with prevalent AF in unselected patients presenting to hospital. Findings should be externally validated. Results suggest that age and different disease processes approximated by these three biomolecules contribute to AF in patients. Our findings have the potential to improve screening programs for AF after external validation. [ABSTRACT FROM AUTHOR]

Background: The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker.Objective: The purpose of this study was to assess whether insulin-like growth factor-binding protein 7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication.Methods: We analyzed 2 prospective multicenter observational cohort studies that included 3691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox regression analyses were constructed.Results: Mean patient age was 69 ± 12 years, 1028 (28%) were female, and 879 (24%) had a history of CHF. The incidence per 1000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32, and 85. The corresponding multivariable adjusted hazard ratios (aHRs) (95% confidence interval [CI]) were 1.0, 1.05 (0.63-1.77), 2.38 (1.50-3.79), and 4.37 (2.72-7.04) (P for trend <.001). In a subgroup of 2812 patients without pre-existing CHF at baseline, the corresponding aHRs were 1.0, 0.90 (0.47-1.72), 1.69 (0.94-3.04), and 3.48 (1.94-6.24) (P for trend <.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20; 3.35-8.09) compared to those with only 1 elevated marker (elevated IGFBP-7 aHR 2.17; 1.30-3.60); elevated NT-proBNP aHR 1.97; 1.17-3.33); or no elevated marker (reference).Conclusion: Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP. [ABSTRACT FROM AUTHOR]

Objective: To evaluate blood‐based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014–April 2018). Methods: This prospective, non‐interventional study assessed the diagnostic accuracy of 54 blood‐based biomarker immunoassays in samples from 919 women (aged 18–45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology‐free symptomatic controls". The main outcome measure was receiver operating characteristic‐area under the curve (ROC‐AUC) and Wilcoxon P values corrected for multiple testing (q values). Results: CA‐125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600–0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology‐free symptomatic controls", S100‐A12 performed best (AUC 0.692, 95% CI 0.614–0.769, q = 0.001) followed by CA‐125 (AUC 0.649, 95% CI 0.569–0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology‐free symptomatic controls", respectively, the top‐performing biomarkers were sFRP‐4 (AUC 0.615, 95% CI 0.551–0.678, q = 0.045) and S100‐A12 (AUC 0.701, 95% CI 0.611–0.792, q = 0.004). Conclusion: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty. Synopsis: None of the biomarkers or biomarker combinations studied could diagnose or rule out endometriosis/adenomyosis with a high level of certainty. [ABSTRACT FROM AUTHOR]

Background: Patients with atrial fibrillation (AF) face a high risk of heart failure (HF) hospitalizations. Unfortunately, little data is currently available on the underlying mechanisms of this relationship. Insulin-Like Growth Factor-Binding Protein-7 (IGFBP7) has been associated with worsening HF and cardiac hypertrophy, and is therefore an interesting target in this context. Methods: We performed a prospective multicenter observational cohort study of 1484 patients with documented AF. Information on personal characteristics and co-morbidities was obtained through standardized questionnaires. Baseline IGFBP7 levels were measured from frozen plasma samples. The primary endpoint of this analysis was hospitalization for acute HF, and all events were independently confirmed. Multivariable adjusted Cox regression analyses were constructed to assess the relationship of IGFBP7 levels with incident HF and to adjust for covariates. Results: Mean age was 69±12 years, 435 (29.3%) were females and 302 (20.4%) had a history of HF at baseline. During a mean follow-up of 4.3±1.6 years, 144 confirmed cases of HF hospitalizations occurred. The rate of HF hospitalizations across increasing IGFBP7 quartiles was 5, 6, 20 and 74 per 1000 patient-years of follow-up. The multivariable adjusted hazard ratios [95% CI] across increasing quartiles of IGFBP7 were 0.9 [0.4; 2.1], 2.0 [0.9; 4.5], and 5.3 [2.5; 11.6] (p for trend <0.0001) (Table). Among patients without HF at baseline, the hazard ratios [95% CI] across increasing quartiles of IGFBP7 were 1.0 [0.4; 2.6], 0.7 [0.3; 2.1], and 3.3 [1.3; 8.1] (p for trend <0.0001) (Table). The corresponding incidence rates were 5, 6, 7 and 51 per 1000 patients-years of follow-up. Conclusion: Increasing levels of IGFBP7 were strongly and independently associated with HF hospitalizations in patients with AF, suggesting that cardiac hypertrophy is a major factor in the tight relationship between AF and HF. Given the strength of the association, IGFBP7 may become a useful marker to identify AF patients at increased risk of incident HF. [ABSTRACT FROM AUTHOR]