Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] Show more
Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] measurements to the RF-CL model improves predictions of obstructive CAD. In a derivation cohort (N = 4262; 54% male; mean age 58 years), the prevalence of obstructive CAD at invasive angiography with fractional flow reserve was assessed by Lp(a)-strata. On the basis of initial results, an Lp(a)-adjusted model (RF-CLLp(a)) was developed: RF-CL was multiplied by 1.5 in patients with elevated Lp(a) (≥125 nmol/L) and otherwise unchanged. Discrimination, calibration, and reclassification were compared. Findings were validated in an external validation cohort (N = 1595; 49% male; mean age 60 years) using a comparative endpoint; significant stenosis at invasive angiography or coronary computed tomography.In the derivation cohort, 473 patients (11.1%) had obstructive CAD; in the validation cohort, 206 patients (12.9%) had significant stenosis. The relative risk in patients with elevated Lp(a) was 1.51 [95% confidence interval (CI) 1.23-1.86] and 1.19 (95% CI 0.88-1.60) in the derivation and validation cohort, respectively. In the derivation cohort, the RF-CLLp(a) model showed a higher area under the receiver operating curve than the RF-CL model [0.743 (standard error 0.011) vs. 0.740 (0.013)] and better calibration in patients with elevated Lp(a). Reclassification from RF-CL to RF-CLLp(a) improved likelihood stratification in the derivation cohort but not in the validation cohort. Adding elevated Lp(a) as a risk factor to the RF-CL model improves accuracy of obstructive CAD in patients with high Lp(a). Show less
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and Show more
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Show less