Background Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary... Show moreBackground Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes. Methods Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression. Results Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 +/- 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15). Conclusion The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease. Show less
Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are... Show moreBackground: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility. Show less
Aims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70... Show moreAims The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70 years in four geographical risk regions.Methods and results Sex-specific competing risk-adjusted models for estimating CVD risk (CVD mortality, myocardial infarction, or stroke) were derived in individuals aged over 65 without pre-existing atherosclerotic CVD from the Cohort of Norway (28 503 individuals, 10 089 CVD events). Models included age, smoking status, diabetes, systolic blood pressure, and total- and high-density lipoprotein cholesterol. Four geographical risk regions were defined based on country-specific CVD mortality rates. Models were recalibrated to each region using region-specific estimated CVD incidence rates and risk factor distributions. For external validation, we analysed data from 6 additional study populations {338 615 individuals, 33 219 CVD validation cohorts, C-indices ranged between 0.63 [95% confidence interval (CI) 0.61-0.65] and 0.67 (0.64-0.69)}. Regional calibration of expected-vs.-observed risks was satisfactory. For given risk factor profiles, there was substantial variation across the four risk regions in the estimated 10-year CVD event risk.Conclusions The competing risk-adjusted SCORE2-OP model was derived, recalibrated, and externally validated to estimate 5- and 10-year CVD risk in older adults (aged 70 years or older) in four geographical risk regions. These models can be used for communicating the risk of CVD and potential benefit from risk factor treatment and may facilitate shared decision-making between clinicians and patients in CVD risk management in older persons. Show less
Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals... Show moreAims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe. Show less
Background The Framingham hypertension risk score is a well-known and simple model for predicting hypertension in adults. In the current study, we aimed to assess the predictive ability of this... Show moreBackground The Framingham hypertension risk score is a well-known and simple model for predicting hypertension in adults. In the current study, we aimed to assess the predictive ability of this model in a Middle Eastern population.MethodsWe studied 5423 participants, aged 20-69years, without hypertension, who participated in two consecutive examination cycles of the Tehran Lipid and Glucose Study (TLGS). We assessed discrimination based on Harrell's concordance statistic (c-index) and calibration (graphical comparison of predicted vs. observed). We evaluated the original, recalibrated (for intercept and slope), and revised (for beta coefficients) models.ResultsOver the 3-year follow-up period, 319 participants developed hypertension. The Framingham hypertension risk score performed well in discriminating between individuals who developed hypertension and those who did not (c-index=0.81, 95% CI: 0.79-0.83). Initially, there was a systematic underestimation of the original risk score (events predicted), which was readily corrected by a simple model revision.ConclusionsThe revised Framingham hypertension risk score can be used as a screening tool in public health and clinical practice to facilitate the targeting of preventive interventions in high-risk Middle Eastern people. Show less
Background The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age,... Show moreBackground The multi-biomarker disease activity (MBDA) test measures 12 serum protein biomarkers to quantify disease activity in RA patients. A newer version of the MBDA score, adjusted for age, sex, and adiposity, has been validated in two cohorts (OPERA and BRASS) for predicting risk for radiographic progression. We now extend these findings with additional cohorts to further validate the adjusted MBDA score as a predictor of radiographic progression risk and compare its performance with that of other risk factors.MethodsFour cohorts were analyzed: the BRASS and Leiden registries and the OPERA and SWEFOT studies (total N =953). Treatments included conventional DMARDs and anti-TNFs. Associations of radiographic progression (Delta TSS) per year with the adjusted MBDA score, seropositivity, and clinical measures were evaluated using linear and logistic regression. The adjusted MBDA score was (1) validated in Leiden and SWEFOT, (2) compared with other measures in all four cohorts, and (3) used to generate curves for predicting risk of radiographic progression.ResultsUnivariable and bivariable analyses validated the adjusted MBDA score and found it to be the strongest, independent predicator of radiographic progression (Delta TSS >5) compared with seropositivity (rheumatoid factor and/or anti-CCP), baseline TSS, DAS28-CRP, CRP SJC, or CDAI. Neither DAS28-CRP, CDAI, SJC, nor CRP added significant information to the adjusted MBDA score as a predictor, and the frequency of radiographic progression agreed with the adjusted MBDA score when it was discordant with these measures. The rate of progression (Delta TSS >5) increased from <2% in the low (1-29) adjusted MBDA category to 16% in the high (45-100) category. A modeled risk curve indicated that risk increased continuously, exceeding 40% for the highest adjusted MBDA scores.ConclusionThe adjusted MBDA score was validated as an RA disease activity measure that is prognostic for radiographic progression. The adjusted MBDA score was a stronger predictor of radiographic progression than conventional risk factors, including seropositivity, and its prognostic ability was not significantly improved by the addition of DAS28-CRP, CRP, SJC, or CDAI. Show less
Aalst, C.M. van der; Denissen, S.J.A.M.; Vonder, M.; Gratama, J.W.C.; Adriaansen, H.J.; Kuijpers, D.; ... ; Koning, H.J. de 2020
Aim Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease-related morbidity and mortality. ROBINSCA (Risk Or Benefit... Show moreAim Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or coronary artery calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial.Methods and results Individuals at expected elevated CVD risk were randomized into screening arm A (n = 14 478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n= 14 450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. A total of 12 185 participants (84.2%) in arm A and 12 950 (89.6%) in arm B were screened. In total, 48.7% were women, and median age was 62 (interquartile range 10) years. SCORE screening identified 45.1% at low risk (SCORE < 10%), 26.5% at intermediate risk (SCORE 10-20%), and 28.4% at high risk (SCORE >= 20%). According to CAC screening, 76.0% were at low risk (Agatston < 100), 15.1% at high risk (Agatston 100-399), and 8.9% at very high risk (Agatston >= 400). CAC scoring significantly reduced the number of individuals indicated for preventive treatment compared to SCORE (relative reduction women: 37.2%; men: 28.8%).Conclusion We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. Show less
Aims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention... Show moreAims There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29 39% of individuals aged >= 40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44 51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms.Conclusion Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. Show less
